Expired RFA-HD-06-020: Cooperative Multicenter Diabetes Research Network for Hypoglycemia Prevention (U10)

Department of Health
and Human Services (HHS)

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EXPIRED

Part I Overview Information

Department of Health and Human Services

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

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

Title: Cooperative Multicenter Diabetes Research Network for Hypoglycemia Prevention (U10)

Announcement Type
This is a reissue of RFA-HD-05-052, which was previously released February 27, 2006.

Request For Applications (RFA) Number: RFA-HD-06-020

Catalog of Federal Domestic Assistance Number(s)
93.865, 93.853, 93.847

Key Dates
Release Date: October 10, 2006
Letters of Intent Receipt Date(s): October 23, 2006
Application Receipt Date(s): November 22, 2006
Peer Review Date(s): February/March 2007
Council Review Date(s): June 2007
Earliest Anticipated Start Date(s): July 1, 2007
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: November 23, 2006

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

The National Institute of Child Health and Human Development (NICHD). National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite applications from investigators willing to participate in a cooperative research network designed to reduce the incidence of hypoglycemia in children and young adults.
The Diabetes Research in Children Network (DirecNet) currently consists of five academic centers were selected from among respondents to a previous announcement (RFA-HD-01-009) to support a network focusing on glucose monitoring in children. This RFA serves to expand the mission of DirecNet. The network will use new tools to evaluate factors and mechanisms contributing to hypoglycemia and will set up clinical trials to test novel therapies, prevention strategies and devices designed to focus on hypoglycemia prevention for individuals with type1 diabetes.
It is anticipated that a maximum of five awards for Clinical Centers (CCs) and one award for a Data Coordinating Center (DCC) will be made. Approximately $2 million (total costs) [Direct plus Facilities and Administrative (F & A) costs] will be appropriated from the Balanced Budget Act Funds for Type 1 Diabetes. This commitment is contingent upon the availability of funds.
This funding opportunity will use the NIH Cooperative Clinical Research (U10) award mechanism for both the DCC and the CCs.
A CC applicant may request a project period of up to five years and an annual budget for direct costs associated with base costs up to $140,000 per year.
A DCC applicant may request a project period of up to five years and an annual budget up to $425,000 direct costs. In addition, the DCC should request not more than $350,000 total costs per year for the distribution of per subject/per protocol costs to the Clinical Centers for approved protocols.
A CC applicant may request a project period of up to five years and an annual budget for direct costs associated with base costs up to $140,000 per year.
A DCC applicant may request a project period of up to five years and an annual budget up to $425,000 direct costs. In addition, the DCC should request not more than $350,000 total costs per year for the distribution of per subject/per protocol costs to the Clinical Centers for approved protocols.
Eligible organizations include non-profit organizations; for profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units of State government ; units of local government ; eligible agencies of the Federal government ; and domestic institutions.
Eligible principal investigators include Principal Investigators include those with the experience and expertise to conduct clinical studies in type1 diabetes. Individuals with expertise in endocrinology are encouraged to apply. Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
An applicant institution may apply for both a Clinical Center and a Data Coordination Center award under this RFA, but the applications for each must be from different Principal Investigators and must be submitted as separate applications.
Applicants may submit more than one application, provided they are scientifically distinct.
See Section IV.1 for application materials.
Telecommunications for the hearing impaired is available at: TTY 301-451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
  1. Research Objectives

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

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

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

Section V. Application Review Information
  1. Criteria
  2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Sharing Research Data
    D. Sharing Research Resources
  3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
  1. Award Notices
  2. Administrative and National Policy Requirements
    A. Cooperative Agreement Terms and Conditions of Award
      1. Principal Investigator Rights and Responsibilities
      2. NIH Responsibilities
      3. Collaborative Responsibilities
      4. Arbitration Process
  3. Reporting

Section VII. Agency Contact(s)
  1. Scientific/Research Contact(s)
  2. Peer Review Contact(s)
  3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

The purpose of this Request for Applications (RFA) is to establish a research network that will contribute to improved management of type1 diabetes and hypoglycemia prevention. The National Institute of Child Health and Human Development (NICHD), National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite applications from investigators willing to participate in a cooperative research network designed to reduce the incidence of hypoglycemia in children and young adults. The network will use new tools to evaluate factors and mechanisms contributing to hypoglycemia and will set up clinical trials to test novel therapies, prevention strategies and devices designed to focus on hypoglycemia prevention for individuals with type 1 diabetes. The clinical research network will provide the necessary infrastructure to develop, coordinate, and conduct multiple collaborative clinical protocols. Results of network studies are expected to be widely disseminated and to improve the scientific basis of care for individuals affected with type1 diabetes. NIH project scientists will assist Principal Investigators of the research network in identifying research topics of high priority, and in designing and implementing protocols in the evaluation and implementation of optimum management of type1 diabetes. It is anticipated that approximately five clinical centers will participate in the program.

Background

The primary objective of the research network is to advance the field of hypoglycemia prevention by establishing and maintaining a network of academic centers that perform multi-center clinical protocols to investigate the safety and efficacy of treatment and management strategies to care for patients with type1 diabetes. This solicitation is part of a multi-faceted research program at the NIH intended to reduce morbidity and mortality in patients with type1 diabetes.

Hypoglycemia continues to be the major limiting factor in achieving near normalization of blood glucose in individuals with type1 diabetes. Results of the Diabetes Control and Complications Trial demonstrated that near-normalization of blood glucose levels can be achieved through intensive therapy and reduces the risk of developing the microvascular complications frequently associated with diabetes. Although the same regimen and glycemic goals were imposed on both adults and adolescents, the latter group was distinctive in their response to the treatment regimen. Intensive treatment in adolescents caused a three-fold greater risk for severe hypoglycemia and a two-fold increased risk for obesity compared to similarly treated adults with diabetes. Treatment induced (iatrogenic) hypoglycemia, a cause of recurrent morbidity and sometimes mortality, remains a crucial problem for most type1 diabetics. The incidence and severity of hypoglycemia may be increased in younger children. Additionally, children with recurrent episodes of hypoglycemia may be at increased risk for learning disabilities and behavior problems.

Nighttime hypoglycemic episodes are more frequent and longer in duration suggesting a sleep related mechanism may be involved. An episode of hypoglycemia impairs defenses against subsequent hypoglycemia and thus causes a vicious cycle of recurrent hypoglycemia. Further insights into the mechanisms underlying impaired counterregulatory hormone responses and hypoglycemia unawareness are needed. Further evaluation is needed of the adaptive changes in brain metabolism and function following recurrent hypoglycemia. Inadequate blood glucose monitoring systems represent yet another important part of the problem inherent to conventional diabetes management. Several technologies have emerged over the past years with much potential to improve type 1 diabetes management. For example, novel continuous monitoring systems and new drug delivery methods are areas that require further clinical testing and development. Continuous monitoring systems have the potential to identify the true incidence, magnitude and duration of hypoglycemic episodes experienced by diabetics. These devices will eventually enable researchers to move toward a closed loop monitoring-delivery system.

Scope

There are a number of issues in the area of hypoglycemia prevention in type1 diabetes that might be clarified by multicenter collaborative research. Specific projects will focus predominantly but not exclusively on children. The inclusion of adults is encouraged, especially in protocols designed to test new investigational drugs or devices. The participating research network members will identify research topics of high priority, recruit, assess and treat subjects under the supervision of the respective CC Principal Investigator. The DCC will have primary responsibility for data management and analysis for network research in collaboration with the Steering Committee.

Examples of Research Topics

Individual grant applicants should propose a unique clinical research protocol pertaining to type1 diabetes management and hypoglycemia prevention. Specific projects should be included based on their importance in the field, need for a multi-center approach, and feasibility. Principal Investigators are encouraged to include collaborators at their sites with expertise appropriate to the research objectives, including neuroscience, neuroimaging, physiology, nutrition or other relevant areas of research.

Some examples of research topics appropriate for this RFA include, but are not limited to, the following:

• Determine therapeutic strategies that will reduce the risk of iatrogenic hypoglycemia.

• Evaluate the underlying mechanisms of hypoglycemia unawareness.

• Differentiate daytime and nighttime hypoglycemia and determine if circadian or sleep mechanisms are involved.

• Evaluate advances in the use of existing or new non-insulin-based pharmacologic agents.

• Evaluate novel drug delivery methods for prevention of hypoglycemia and treatment of diabetes.

• Develop and/or evaluate improved minimally invasive blood glucose monitoring technologies for use as a tool to reduce the incidence of hypoglycemia.

These are examples only. Applicants are not limited to the topics mentioned above and are encouraged to submit their individual topic pertinent to the objectives of the RFA. Multiple studies will be conducted simultaneously. Network studies may be selected from those proposed by the successful applicants, but a decision to fund a particular CC will not commit the network to develop that group's clinical protocol. The NICHD expects to enable the network to initiate new protocols within the first year of the award period. The topics of these protocols will be decided cooperatively by the Steering Committee with advice from the Protocol Review Committee (PRC).

Organization of the Research Network

The research network will be a cooperative clinical network consisting of up to five Clinical Centers (CCs), a Data and Coordinating Center (DCC), and the NIH (NICHD, NINDS, NIDDK). The network organization will include a steering committee, a protocol review committee, and a data and safety monitoring board. The responsibilities of each component of the network are described below.

Clinical Centers (CCs)

The CCs will propose protocols, participate in their overall development, recruit and enroll subjects in ongoing concurrent network protocols, conduct the protocols, and disseminate research findings. All individual CC will be required to participate in a cooperative and interactive manner with one another and with the DCC. The CCs will likely be major medical centers with existing relationships with private or community hospitals and physician practices. It is expected that individual CC will vary in nature and experience, and thus may represent both different patient populations and unique expertise in the area of type1 diabetes management and hypoglycemia prevention. The CCs must demonstrate excellence in designing and executing clinical trials and a proven ability to recruit patients from various racial/ethnic groups. Each CC is expected to enroll a minimum of 10% the total number of subjects needed to perform the proposed collaborative study, as determined by the Steering Committee. The Principal Investigator (PI) at each CC will be responsible for proposing protocols, estimating their costs, and participating in their overall development; conducting the research; assuring quality of patient care and protocol adherence; assuring the accurate and timely transmission of data collected in conjunction with the DCC; and disseminating research findings. Each CC will be subject to annual administrative review.

Data Coordinating Center (DCC)

The DCC will coordinate, administer, and support all network research activities. These activities include, but are not limited to, administrative support for the network chair and scientific advisory committees; reimbursement for patient accrual; and organization of investigator meetings. The DCC will assist in final protocol development, provide statistical guidance for each study design, and prepare operational timetables. The DCC will develop a data collection system and manuals of operations, determine sampling and randomization schemes, and assist in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC will also provide regulatory guidance and facilitate interactions with regulatory authorities. The DCC will subcontract with external laboratories as needed and arrange for standardization and quality control measures. The DCC will manage and distribute all funding for a centralized core laboratory.

The DCC will develop procedures for quality control, training and certification, and data management. It will monitor the quality and quantity of data received from the CC, provide relevant reports to the NIH, CCs and SC, and serve as a central repository for study data. The DCC is responsible for any site visits necessary for training, quality control, data management and, at a minimum, will visit each site once in the course of the study period. The DCC will prepare confidential data analyses and reports for the DSMB. The DCC will support manuscript preparation through data analysis, statistical consultation, editorial support, and meeting coordination. It will schedule and make arrangements for all meetings of established committees. The DCC will manage and distribute protocol funds to participating CCs as patients are enrolled and study criteria is met as a per-subject/per protocol arrangement after a protocol has been approved and the NIH has released the funds for distribution.

Steering Committee (SC)

The SC will be the main governing body of the network. Voting members of the SC include, at a minimum, the network chair, the PIs of the CCs and of the DCC (or their designated alternates) and the NIH project scientists (from NICHD, NIDDK, and NINDS), who will have one NIH vote. The SC Chair will be one of the PIs. The SC Chair will plan network activities, oversee its functions, conduct SC meetings, and be a voting member of the SC. The SC will develop and ensure compliance with network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the CCs for submission to the PRC. The SC will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, and that study results are reported in the scientific literature in a timely manner and disseminated to those directly involved in the care of diabetes patients. The SC may meet four times in the first 12 months of the study, two times per year thereafter, and by teleconference on a biweekly basis. All major scientific decisions will be determined by majority vote of the SC. The SC has final responsibility for approving the protocol before review by the PRC or DSMB. Subcommittees of the SC will include a Publications and Presentations Subcommittee and a Quality Control Subcommittee. The Publications and Presentations Subcommittee will facilitate and supervise preparation of manuscripts prior to submission for publication. The Quality Control Subcommittee will be responsible for developing standards for specific laboratory tests and other measures to be used in the network protocols.

Protocol Review Committee (PRC)

The PRC will consist of a chairperson and scientists outside of the network, who have expertise in basic and clinical Type1 Diabetes research, neuroscience, clinical trial design, biostatistics, enabling technologies, outcome measures, and other areas of expertise as needed. The PRC will be appointed by the NICHD, with advice from the NIDDK and NINDS project scientists.

The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the SC. The PRC will evaluate protocols proposed by the SC based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the Network and consistency with NIH missions and policies. All study protocols performed by the Network must be recommended by the PRC and approved by the NIH before initiation.

Data Safety and Monitoring Board (DSMB)

NIH Staff

NIH staff will include Project Scientists from NICHD, NINDS and NIDDK and an NICHD program officer (see Section VI.2 below).

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

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U10 award mechanism(s).

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH (U10) is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

NICHD intends to commit approximately $2 million dollars (total costs) in FY 2007 from the Special Statutory Funding Program for Type 1 Diabetes Research administered through the NIDDK in order to fund five CC and one DCC grants for a period of five years in response to this RFA.
A DCC applicant may request a project period of up to five years and an annual budget up to $425,000 direct costs. In addition, the DCC should request not more than $350,000 total costs per year for the distribution of per subject/per protocol costs to the Clinical Centers for approved protocols.
Clinical Center awards will be for core infrastructure costs, excluding the cost of implementing the proposed protocols, which will be distributed to the Clinical Centers through the DCC on a per subject/per protocol basis as patients are enrolled and study criteria is met. An applicant may request a project period of up to five years and direct costs up to $140,000 for the first year.
The anticipated start date of the awards is July 1, 2007.

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

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

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

Non-profit organizations
For profit organizations
Public or private institutions, such as universities, colleges, hospitals, and laboratories
Units of State government
Units of local government
Eligible agencies of the Federal government
Domestic Institutions only

1.B. Eligible Individuals

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

2. Cost Sharing or Matching

Not applicable

3. Other-Special Eligibility Criteria

Awards for a Clinical Center and a DCC will not be made to the same Principal Investigator to ensure that data analysis is performed independently of data acquisition. The same institution may apply for both a Clinical Center and a DCC award, but the applications for each must be from different individuals and must be submitted as separate applications.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times

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

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date(s): October 23, 2006
Application Receipt Date(s): November 22, 2006
Peer Review Date(s): February/March 2007
Council Review Date(s): June 2007
Earliest Anticipated Start Date(s): July 1, 2007

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research
Name, address, and telephone number of the Principal Investigator
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Karen K. Winer, M.D.
Endocrinology, Nutrition and Growth Branch
National Institute of Child Health and Human Development
6100 Executive Blvd Room 4 B-11A
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: (301) 435-6877
FAX: 301-480-9791
Email: [email protected]

3.B. Sending an Application to the NIH

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

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

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

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

Robert Stretch, PhD
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: 301 496-1485
FAX: 301 402-4104
Email: [email protected]

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review.
Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by NICHD. Incomplete and non-responsive applications will not be reviewed.

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

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

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

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

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

Special Requirements

The Network will be a collaborative effort that will require all individual CC to participate in a cooperative and interactive manner with each other, the DCC, and with the NICHD. Applicants should explicitly indicate their willingness to:

Participate in SC meetings, site visits, and regular telephone conference calls.
Cooperate with other awardees in the development and design of research protocols.
Abide by common methods for patient selection and enrollment, and common protocols, procedures, tests, and reporting forms as chosen by majority vote of the SC.
Actively implement each network-wide protocol approved by the PRC and NIH staff.
Comply with study policies and quality assurance measures approved by the SC.
Agree to oversight of the study by a DSMB.
Accept funds from the DCC for the support of research based on per-patient (capitated) rates and actual numbers of subjects enrolled, followed, and completing the study (CCs only).
Accept, manage, and distribute funds for the support of research based on the number of protocols developed, initiated, and carried out (DCC only).
Transmit study data to the DCC in a timely and accurate manner (CCs only).
Report all adverse events in accordance with procedures established by the SC and NIH policies.
Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources.
Accept the Cooperative Agreement Terms and Conditions of Award which are found in Section VI, Award Administration Information.

Clinical Center (CC) Applicants

Expectation of Cooperation: To promote development of a collaborative program among the award recipients, the issues discussed below need to be addressed in each application for a CC. Applicants must indicate their willingness and ability to participate in the stated aspects of the network.

Qualifications and Experience

Minimum Requirements: The following items must be addressed satisfactorily for an applicant to be eligible for consideration as a clinical site:

The Principal Investigator must be a practicing endocrinologist/diabetologist who is able to make a long-term commitment of effort to network responsibilities.
There must be two investigator-scientists at each clinical site who will receive salary support. This includes the Principal Investigator and one other investigator who may have expertise in diabetes or an allied field relevant to this RFA, such as neuroscience.
The clinical site must be located in an institution with a full spectrum of clinical specialists involved in the care of type1 diabetes.
The clinical site must be able to enroll a minimum of 10% of the subjects per year that are proposed for the network protocols.

Applicants for CCs must have the experience and expertise to conduct complex multi-center clinical studies and a history of previous successful clinical research. Prospective CCs must have an established research program in the scientific areas of interest and demonstrated access to a sufficient number of patients to accomplish their portion of the proposed protocols. The applicant must have an established program with experience in identifying and treating patients with type1 diabetes and a designated facility for this purpose. CC applicants should also discuss clinical studies and trials conducted in last two years, particularly those related to type1 diabetes. Applicants should be well-versed in the science of hypoglycemia pathophysiology and prevention. The applicant must demonstrate the willingness and the ability to participate in a cooperative manner with other CCs, the DCC, and the NIH in the development of research protocols, statistical methods, uniform data collection and data transfer.

A minimum time commitment of 25% is expected from the physician leadership (from Principal Investigator and any co-investigators, combined) at each CC. The Principal Investigator must have a demonstrated track record of successful leadership of a multi-disciplinary team, including the ability to communicate with and ensure collaboration among endocrinologists and related subspecialists, such as neuroscience. Each CC must designate a research coordinator with adequate percent effort as described below. A description of this individual's training, experience and involvement in clinical research should be provided.

Clinical Research Protocols

Estimated clinical protocol implementation costs should be based on the proposals presented in the applicant's research plan, but should not be included in the CC budget request. A table must be included showing estimated costs per patient for conducting each proposed protocol. The budget for each protocol must be developed on a cost-per-patient basis and include all direct costs and the associated protocol facilities and administrative costs. A description of the method/formula used to estimate the cost per-patient should be included. Costs of drugs or laboratory tests should be part of the per-patient cost of conducting a protocol. The applicant should delineate how blood specimens will be handled and analyzed. If a central laboratory is required to analyze blood specimens, the cost of obtaining them will be part of the CCs per-patient expense. The cost of shipping, analyzing, and storage, as well as training of personnel and quality control will be the responsibility of the DCC. Costs to implement the protocol should be identified in the research plan. It is anticipated that the first six months will be devoted to protocol development with patient recruitment commencing later in the first year. This should be reflected in the proposed budget structure.

Per-patient protocol costs include expenses associated with the conduct of a specific protocol, such as:

Screening of patients to determine study eligibility.
Imaging studies that are not performed as part of routine clinical care.
Laboratory tests that are not part of routine clinical care.
Clinic visits that are not part of routine clinical care.
Expenses associated with family or patient travel, such as mileage, parking, meals, or housing.
Modest patient incentives to encourage enrollment and retention can be included within the limits set by local IRBs.
Specialized consultation.
Study supplies.

The DCC will be responsible for distributing the per-patient funds among the CCs in proportion to recruitment. CCs are asked to develop a per-patient budget for their proposed protocol as part of their application. Investigators should prepare budgets only for their own Clinical Center to conduct the proposed protocols and not for the entire research network. Tests and clinic visits performed as part of routine clinical diabetes care can be incorporated into a research protocol, but their costs will be billed to third-party payers.

Note that ongoing annual budgets for protocols will be based on the protocols approved by the PRC and the SC. Continuation and level of funding for each CC will be based on actual recruitment and overall performance. The precise number of protocols conducted over the five years will be determined by the network SC and will depend on a number of factors, including scientific priority, availability of funds, complexity and protocol requirements.

The applicant should plan and budget for two members of the investigative team to attend up to four SC meetings in year one, and two SC meeting per year in Bethesda, MD, thereafter. Each meeting will be approximately one day in length. Page limit for sections a-d of the CC will be 25 pages.

Concept Proposal

To provide peer reviewers and the NICHD an idea of capabilities of individual investigators, a unique clinical protocol should be described in the application including hypothesis, specific aim(s), background, methods, and data analysis (including a consideration of power). The proposed clinical trial will also serve as an indicator of the individual applicant's ability to participate in the development and design of cooperative protocols in the network. The proposed protocols may be implemented within the network at the request of the PI and approval of the network’s Steering Committee. Page limit for the concept proposal is 25 pages.

Data and Coordinating Center (DCC)

Qualifications and Experience

Applicants for a DCC must demonstrate experience in the conduct of multi-center clinical studies, coordinating all phases of multi-center clinical studies, protocol and manual of operations development, data collection and management, data safety and confidentiality, adverse events, quality assurance, data analysis, distributed data entry, electronic communications, and administrative management and coordination. DCC applicants should describe the method/formula to be used to calculate operational costs per protocol and per enrolled subject for all DCC and CC functions. In addition, describe in detail the proposed system for holding, distributing, and accounting for per protocol funds to be distributed by the DCC to the CC for approved protocols. Page limit for sections a-d in the DCC will be 25 pages.

Study Design and Management

DCC applicants should discuss various aspects of study design that would be important in developing clinical protocols, for example: eligibility criteria; methods of randomization; important considerations for determining sample size and power calculations; determining frequency of data collection; monitoring accuracy of data collection and data entry; quality control procedures including training and certification for multiple protocols, and plans for statistical analysis. In addition, they should describe their plans for administrative management of the DSMB, the PRC, the SC, and associated subcommittees. A plan also should be included for the development and maintenance of a web site with both public and secure components that would include information for patients and investigators. Quality assurance and quality control procedures through a central laboratory under the auspices of the DCC should be instituted across CC. This will include development of a manual of operations, training of staff members from CC.

Budget Information

Clinical Centers

The instructions for the budget requests provided with the research grant application (PHS 398) should be followed. F & A costs will be awarded in the same manner as for research project grants. Allowable costs and policies governing the research grants program of the NIH will prevail. In planning the budget section of your application, each CC applicant should submit the base budget estimate for all years. For purposes of the grant application, CC will be asked to submit separate budgets for core infrastructure budget costs as well as for per-patient costs to conduct the protocol proposed. The per-patient budget is to be included as an example only to facilitate peer review of the application. During the grant cycle covered by this RFA, all patient costs will be awarded to the DCC, which will then be responsible for distributing them to CC once per-patient budgets are approved for each protocol and recruitment begins.

Clinical Center infrastructure budget costs may not exceed $140,000 direct costs, and include:

A minimum total effort of 25% for the physician leadership. A minimum of 10% effort for each person is required (co-investigators and Principal Investigator). Co-investigators can not to exceed 50% effort total.
Up to 100% effort for a nurse coordinator. This effort can be for an individual or can be shared among two individuals and can be phased in as needed for protocol coordination.
Travel for the Principal Investigator and the nurse coordinator to attend up to four SC meetings in year one, and two SC meeting per year thereafter. SC meetings are held in Bethesda, MD.
Supplies and equipment.

The clinical center applicant will be required to accept capitated protocol budgets for those studies underway in the network. These budgets will consist of specific protocol related allowances and will be capitated on the anticipated number of subjects to be enrolled in each study at the applicant clinical site. Ongoing annual budgets will be based on protocols implemented. Each clinical site will be given base costs from NICHD in addition to funding from the DCC that represents protocol costs, i.e. a flat fee for each subject successfully enrolled and completed for each study. For centers with GCRC funding, applicable capitation funds can be reduced relative to the amount of the GCRC support. The Principal Investigator will be required to predict subject enrollment for each specific protocol during a specific time frame, although continuation and level of funding will be based upon actual enrollment. The base budgets for future years should be limited to the first year base budget costs, with an annual increment of base salary and travel costs not to exceed three percent.

Data Coordinating Center

The budget justification for each year should include a table that distributes the direct costs among the following categories: core costs, costs of protocol initiation, and costs of protocol support as described in the RFA. DCC applicants should assume that one to two protocols will be initiated and active in the first year. DCC budgets should include, but are not limited to:

A minimum of 20% effort for the PI.
Additional staff as appropriate to the multiple tasks.
Expenses related to managing the DSMB and the PRC. It can be assumed that the DSMB will include about five members and will meet twice a year in Bethesda, MD, and an additional two times per year by conference call. The PRC will meet no more than once a year in person in Bethesda, MD, and two to four times per year by conference call.
SC expenses. The SC meets 4 times the first year and then two times a year and conducts biweekly conference calls and monthly subcommittee calls for each active protocol subcommittee. Travel of SC members will be budgeted by CC.
One site visit to each of five CC and conference call expenses for one conference call per Clinical Center to follow up on any issues.
Expenses associated with procuring and operating a centralized laboratory. The expense of transferring the data or specimens to the central lab, training technicians to obtain the data in a uniform manner, and instituting quality control measures (e.g., provision for re-reading a proportion of the studies to determine accuracy of interpretation) will be included in the DCC budget.
Expenses associated with training the nurse coordinators at the beginning of each protocol.
Support for the network chair at 20% effort, travel to SC and DSMB meetings each year, and modest administrative expenses.
Expenses associated with any computer hardware that may be needed at all sites.
Expenses associated with quality control procedures.
Expenses associated with managing and distributing protocol funds to participating CCs on per patient/per protocol basis.

Applicants for the DCC should prepare budgets for five one-year periods with maximum allowable direct costs for the DCC limited to $425,000 in the first year. Additionally, DCC applicants will receive a total budget of $350,000 per year to conduct protocols. The protocol funds will be used to reimburse the CCs for the costs of recruitment, patient care, devices, and drugs used in the protocols. It is expected that patient costs will be greatest in years two through five. These funds will be managed and distributed by the DCC to each participating CC as patients are successfully enrolled and completed for each study after a protocol has been approved and the NIH has released the funds for distribution.

The budget justification for each year must include a table that apportions the total cost request among the following categories: 1) center costs, 2) costs of protocol initiation (per protocol), and 3) costs of protocol support (per protocol). Center costs should include support for essential personnel and facilities and the costs for meetings in Bethesda, Maryland of the PRC and the DSMB. Costs of protocol initiation should include the costs of developing the procedures manual, questionnaires, forms, and database structures. Protocol support costs should include the costs of pharmaceutical handling, data entry and analysis, quality control, and manuscript preparation. The DCC budget must include support for the network chair over the 5 years (20% effort needed and travel expenses), and also for site visits made to all the CC during the 5- year interval. The total first year budget request should provide for the organization of all administrative aspects of the network and for the development of at least one protocol. The funds released for DCC operations in each year will be based in part on the number of protocols actually carried out by the network and may be more or less than the budget requested in the application.

For budget purposes, DCC applicants should assume that in the first year all administrative aspects of the network will be organized and at least one protocol will be developed. For subsequent years, applicants may assume that at least two protocols a year will be active (either in the protocol development, implementation, or analysis and writing phase). DCC applicants must include costs for coordinating the DSMB, the PRC, and the SC calls and meetings (DSMB meetings will be held two times per year in Bethesda, Maryland), and the administrative expenses of biweekly SC conference calls and up to four SC meetings in Bethesda, Maryland, in year one and two meetings per year thereafter. Costs allowed for the participation of the network chair include salary support (up to 20%), travel expenses, and administrative support. The DCC also needs to include costs for site visits of each of the CCs assuming a three-member site visit team. Cost for financial administration to prepare protocol budgets and to distribute and monitor funds should also be addressed. DCC applications will describe methods to coordinate study planning, implementation and the dissemination of study results. Applications that do not include a dissemination of study results plan will be considered non-responsive and not eligible for review. The awards will be subject to annual administrative review. It is expected that all protocols will be performed in a manner consistent with FDA guidelines.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

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

The following will be considered in making funding decisions:

Scientific merit of the proposed project as determined by peer review
Availability of funds
Relevance of program priorities

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NICHD in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.
Receive a written critique.
Receive a second level of review by an appropriate national advisory council or board.

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Additional Review Considerations for Clinical Center (CC) applications

Significance:

Does the CC application adequately describe the basis of the specific research protocol proposed, and demonstrate the overall ability to participate in a multi-center Network?
Does this study address an important problem? If the aims of the CC application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach:

Does the CC application demonstrate patient access, the relevance and importance of proposed protocols, and an ability to participate in a research network?
Is the study population adequate to carry out network protocols? Are there plans to ensure appropriate representation by ethnic group and gender? Are plans for the recruitment and retention of subjects provided? What is the likelihood that accrual will be accomplished on time given the study population and recruitment plan provided?
Are preliminary results provided that justify the proposed end points and sample size? Is the patient risk-benefit discussed and steps taken to minimize risk addressed? Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?
What is the applicant institution's history of collaborative research, depth of commitment and ability to work with other network centers and the NIH?

Innovation:

Does the CC application demonstrate the innovative qualities of their proposed project? Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators:

Does the CC application demonstrate the qualifications and experience of the investigators and staff, with regard to their expertise, training, and experience in clinical trials, evidence of understanding of randomized, multi-center trials, administrative abilities of the Principal Investigator and the level of commitment to the network?
Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project?

Environment:

Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Additional Review Considerations for the Data and Coordinating Center (DCC) Applications:

Approach:

Does the DCC application demonstrate adequate study management, leadership and understanding of scientific and statistical issues?
Does the application demonstrate an understanding of the scientific, statistical, and technical issues underlying multi-center studies? Is there appropriate study design and statistics, data acquisition and management, data quality control, data analysis, handling and quality control of laboratory specimens, and network coordination?
In terms of study management, are there adequate administrative, supervisory, and collaborative arrangements for achieving the goals of the program, including willingness to cooperate with the participating CCs and the NIH? Does the application demonstrate an ability to assist CCs with recruitment problems to meet enrollment goals?
Does the application provide a plan to determine operational costs per protocol and per enrolled subject and describes a system for distributing and accounting for per protocol funds?
Does the application include a plan for administrative management of the DSMB, the PRC, the SC, and associated subcommittees? Does the plan also include the development and maintenance of a web site with both public and secure components that would include information for patients and investigators?
Does the application include quality assurance and quality control procedures through a central laboratory under the auspices of the DCC? Does it include development of a manual of operations and training of staff members from CC?

Investigators:

Does the DCC application demonstrate the expertise, training, and experience of the investigators and staff, including the administrative abilities of the Principal Investigator, co-investigators, and the time they plan to devote to the program for the effective coordination of the network?
Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise?

Environment:

What is the DCC applicant institution's history of collaborative research and ability to work with CCs and the NIH?
Are the facilities, equipment, and organizational structure adequate to effectively coordinate network activities and assist CCs in implementing the network protocols? This includes obtaining study drugs, investigational agents or devices.

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and

http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information

1. Award Notices

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement (NIH Cooperative Clinical Research Network U10), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2.A.1. Principal Investigator Rights and Responsibilities

Clinical Center(CC)

The Principal Investigator (PI) at each Clinical Center (CC) will be responsible for proposing protocols, estimating their costs, and participating in their overall development; implementing the network protocols; enrolling required number of subjects per protocol; conducting the research; assuring quality of patient care and protocol adherence; assuring the accurate and timely transmission of data collected in conjunction with the DCC; and disseminating research findings. Each CC will be subject to annual administrative review.

CC Network responsibilities. In collaboration with the other awardees and with the assistance from the NIH project scientist(s), the Principal Investigator will have the primary responsibility for:

Identification of priority areas for research
Developing and implementing the network protocols
Collection and transmission of the data to the DCC
Analysis of data and publication of results
Determine anticipated subject enrollment for each protocol; level of funding will be based on actual enrollment.
Coordinating activities of the Steering Committee and the Protocol Review Committee

Data Coordinating Center (DCC)

The DCC will have primary responsibility for data management and analysis for network research in collaboration with the Steering Committee. The DCC will coordinate, administer, and support all network research activities. These activities include, but are not limited to, administrative support for the network chair and scientific advisory committees; reimbursement for patient accrual; and organization of investigator meetings. The DCC will assist in final protocol development, provide statistical guidance for each study design, and prepare operational timetables. The DCC will develop a data collection system and manuals of operations, determine sampling and randomization schemes, and assist in defining primary and secondary outcomes and analytical approaches for the protocols. The DCC will also provide regulatory guidance and facilitate interactions with regulatory authorities. The DCC will subcontract with external laboratories as needed and arrange for standardization and quality control measures. The DCC will manage and distribute all funding for a centralized core laboratory.

All activities of the DCC must be closely coordinated with the SC, the SC Chair and NIH Project Scientists. In support of all research projects, the DCC staff will:

Support the activities of the SC and DSMB through provision of materials/documentation support, meeting planning and logistics, and conference call coordination;
Assist in the preparation, design, and dissemination of operations manuals, data collection forms, databases, and results for research projects;
Compile site visit reports, monthly and quarterly subject enrollment reports, meeting summaries, quarterly CC performance and progress reports, and other reports as needed for the SC, DSMB, NICHD, other participating NIH sponsors.
Maintain or assure maintenance of high quality databases resulting from any collaborative research, supervise all data collection procedures, and arrange for the most efficient transfer of study data where indicated;
Ensure that all CC sites and investigators fully comply with Department of Health and Human Services (DHHS) and NIH requirements, including informed consent, reporting of adverse events, human subject safety and welfare provisions, and inclusion of women, minorities, and children.
Participate in regular conference calls and attend network meetings.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

An NIH Project Scientist (s) will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

The NIH Project Scientist(s) will serve as the principal representative of the NIH and will have substantial programmatic and scientific involvement that is above and beyond the normal stewardship role in awards and will, in consultation with relevant NIH program staff, provide overall programmatic coordination, and assistance to network.

Specifically, the NIH Project Scientist will:

Facilitate communication, cooperation, and the exchange of information among network members and between the network components and other existing programs to support collaborative efforts;
Participate as a voting member of the SC (one vote for NIH);
Consult with NICHD program staff and NIH co-sponsors when needed for optimal implementation of study designs;
Assist the SC in the selection of important research topics and the development and review of protocols for any specific studies;
Assist the SC Chairperson with formation of any SC subcommittees;
Assist in the development and review of fixed protocol budgets, including the identification of study costs and special institutional needs;
Assist in the evaluation of each stage of the program before subsequent stages are started, in conjunction with the SC and the PRC;
Assist in the conduct of the trials, including ongoing review of progress; possible redirection of activities to improve performance and cooperation; and frequent communication with other members of the SC;

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.

The Program Official(s) from NICHD and from the co-sponsoring NIH ICs will:

monitor patient recruitment and study progress, ensure disclosure of conflicts of interest, and ensure adherence to NIH policies.
Assure scientific merit of the trials, including the option to withhold support to a participating institution if technical performance requirements such as protocol compliance, enrollment targets, or randomization of subjects are not met;
Continually review all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines;
Initiate action to modify or terminate a study based on the advice of the DCC, DSMB, PRC and/or the SC, and at the direction of the Director, NICHD

2.A.3. Collaborative Responsibilities

In addition to the above specified rights, responsibilities, and involvement, the Network components have collaborative responsibilities. These include membership on the Steering Committee (SC), and interaction with the Data and Safety Monitoring Board (DSMB).

Steering Committee

The SC will be the main governing body of the network. Voting members of the SC include, at a minimum, the network chair, the PIs of the CCs and of the DCC (or their designated alternates) and the NIH project scientists (from NICHD, NIDDK, and NINDS); NIH will have one vote. The NICHD, NINDS and the NIDDK will select a chairperson from among the non-federal Steering Committee members or other experts in diabetes clinical research. The chairperson of the Steering Committee must not have primary responsibility for recruitment or follow-up of study participants. If a study investigator is chosen as chairperson, he/she must designate a replacement investigator at his/her institution. The chairperson must have proven evidence of leadership ability and be able to make an adequate time commitment to the cooperative agreement. The SC Chair will plan network activities, oversee its functions, conduct SC meetings, and be a voting member of the SC. All major scientific decisions will be determined by majority vote of the SC. The SC has final responsibility for approving the protocol before review by the PRC or DSMB. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

The SC will develop and ensure compliance with network policies and procedures, identify and prioritize topics for investigation, evaluate protocols proposed by the CCs for submission to the PRC. The SC will ensure that studies are properly conducted and monitored, that data are appropriately analyzed and interpreted, and that study results are reported in the scientific literature in a timely manner and disseminated to those directly involved in the care of diabetes patients. The SC may meet four times in the first 12 months of the study, two times per year thereafter, and by teleconference on a biweekly basis.

Subcommittees of the SC will include a Publications and Presentations Subcommittee and a Quality Control Subcommittee. The Publications and Presentations Subcommittee will facilitate and supervise preparation of manuscripts prior to submission for publication. The Quality Control Subcommittee will be responsible for developing standards for specific laboratory tests and other measures to be used in the network protocols.

Protocol Review Committee (PRC)

The PRC will consist of a chairperson and scientists, outside of the network, who have expertise in basic and clinical Type1 Diabetes research, neuroscience, clinical trial design, biostatistics, enabling technologies, outcome measures, and other areas of expertise as needed. The PRC will be appointed by the NICHD, with advice from the NIDDK and NINDS project scientists. The exact number and duration of protocols supported in the five-year program will depend on the nature and extent of the investigations proposed by the SC. The PRC will evaluate protocols proposed by the SC based on the importance of the question to be addressed, scientific merit of the experimental design and approach, feasibility, appropriateness for the Network and consistency with NIH missions and policies. All study protocols performed by the Network must be recommended by the PRC and approved by the NIH before initiation.

Data and Safety Monitoring Board

The Data and Safety Monitoring Board (DSMB) will ensure data quality, participant safety and will collectively judge the appropriateness of continuing each study. In addition, the DSMB will provide a critique of risk to NIH before protocol initiation. The DSMB is established by NICHD to monitor the safety of ongoing clinical trials. It also advises the NIH and the Network, including the Data Coordinating Center, on research design issues, data quality and analysis, and ethical and human subject issues. The DSMB members have expertise in clinical trial design and conduct; relevant basic, medical, and behavioral sciences research; as well as ethical issues.

Each full member will have one vote.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

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

1. Scientific/Research Contacts:

Karen Winer, M.D.
Endocrinology Nutrition Growth Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
FAX: 301-480-9791
Email: [email protected]

2. Peer Review Contacts:

Robert Stretch, PhD
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: 301 496-1485
FAX: 301 402-4104
Email: [email protected]

3. Financial or Grants Management Contacts:

Victoria Bishton
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17C, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 451-5857
FAX: (301) 451-5510
E-mail: [email protected]

Section VIII. Other Information

Required Federal Citations

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

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

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

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

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

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

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

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

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

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

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

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

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

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

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

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

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

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices