CLINICAL ISLET TRANSPLANTATION: DATA COORDINATING CENTER

RELEASE DATE:  December 5, 2003

RFA NUMBER:  RFA-DK-04-004 (Reissued as RFA-DK-09-501)

Department of Health and Human Services (DHHS)
 (http://www.hhs.gov/)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION: 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 (http://www.niddk.nih.gov)
National Institute of Allergy and Infectious Diseases (NIAID/NIH) 
 (http://www.niaid.nih.gov)

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
93.847, 93.855, 93.856 

LETTER OF INTENT RECEIPT DATE: March 16, 2004
APPLICATION RECEIPT DATE: April 13, 2004

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Cooperative Agreement Terms and Conditions of Award
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA
 
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
and the National Institute of Allergy and Infectious Diseases (NIAID) invite 
applications for a Data Coordinating Center (DCC) to participate in a 
consortium of investigators and institutions that will perform clinical 
studies of islet transplantation in patients with type 1 diabetes mellitus 
(T1D).  This consortium will develop and implement a program of single- 
and/or multi-center clinical trials, accompanied by mechanistic studies, in 
islet transplantation with or without accompanying kidney transplantation, 
for the treatment of T1D.  Successful applicants for the DCC, together with 
Clinical Centers (see below), will constitute a Clinical Islet 
Transplantation (CIT) consortium whose aim is to design and implement human 
islet transplantation studies that will result in an improved treatment of 
T1D.  

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

The goals of the consortium, which are elaborated in a complementary 
solicitation (RFA DK-04-005), include the following: 

(1) Develop a scientific agenda for clinical and mechanistic studies in islet 
transplantation that is consistent with the research objectives described in 
this RFA. 

(2) Design and implement studies consistent with the scientific agenda. These 
studies may be performed by single centers within the consortium or by 
multiple centers implementing a single protocol, as required by the study 
design. 

(3) Share information and resources that will advance the field of islet 
transplantation. 
 
Institutions applying to become Clinical Centers under RFA DK-04-005) may also 
apply for the CIT-DCC solicited under this RFA (DK-04-004). In order to ensure 
that data analysis is done independently of data acquisition, the CIT-DCC 
cannot have overlap in personnel with a CIT-CC. An institution may apply for 
both a CIT-CC and the CIT-DCC, but each application must have separate 
principal investigators and include a specific plan documenting how the 
independent operation (i.e., confidentiality of the study-wide data) of each 
unit will be maintained. 

RESEARCH OBJECTIVES

Background

T1D is an autoimmune disease characterized by the destruction of the insulin-
secreting beta cells of the pancreas by cytotoxic T cells.  T1D is difficult 
to control with the current therapies available, and as a result patients may 
suffer devastating consequences including accelerated cardiovascular and 
peripheral vascular diseases, nephropathy, retinopathy, neuropathy, oral 
diseases and premature death.  The incidence of T1D appears to be increasing 
worldwide.  Although the disease may occur at any age, onset peaks prior to 
twenty years of age.  In some populations, approximately one percent of all 
newborns will develop T1D during their lifetime.

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

The NIH has a comprehensive and multifaceted approach to address these 
challenges and foster development of islet transplantation as a cure for T1D.  
The National Center for Research Resources (NCRR) and the NIDDK, along with 
the Juvenile Diabetes Research Foundation (JDRF), have funded the Islet Cell 
Resource Centers (ICRR), a consortium of ten centers whose mission is to 
provide clinical-grade islets for islet transplantation; to optimize harvest, 
purification, and shipment of islets while developing tests that characterize 
the quality and predict the effectiveness of transplanted islets; and to 
provide islets for basic research  (http://www.infosci.coh.org/icr).  The 
NIDDK also supports the Collaborative Islet Transplant Registry (CITR), which 
collects, analyzes, and disseminates comprehensive and current data on all 
islet/beta cell transplants performed in the United States and Canada   
(http://spitfire.emmes.com/study/isl/index.html).  The Immune Tolerance 
Network, funded by NIAID, NIDDK and JDRF, supports multi-center and single 
center clinical trials of islet cell transplantation 
(http://www.immunetolerance.org/research/islet/trials.html).  Other 
components of this effort include the Non-Human Primate Islet Transplantation 
Consortium 
(http://www.niddk.nih.gov/fund/diabetesspecialfunds/consortia/NHP.pdf), the 
Beta Cell Biology Consortium (http://www.betacell.org), and the Type 1 
Diabetes Rapid Access to Interventional Development (T1D-RAID) 
(http://www.niddk.nih.gov/fund/diabetesspecialfunds/T1D-RAID/).  

Objectives and Scope

The purpose of this RFA is to support a Data Coordinating Center for a 
program of cooperative clinical trials in islet transplantation with 
associated mechanistic studies.  Applicants to the companion RFA, which 
solicits applications from clinical centers, may propose clinical studies 
(single-center pilot studies investigating an innovative approach, or multi-
center validation of single-center experiences) to evaluate:

1. Increasing the efficiency of islet transplantation, with the goal of 
achieving successful single-donor islet transplantation.  Approaches could 
include, but are not limited to, the following:  innovation or refinement of 
procedures for islet isolation; improvement in donor selection criteria; 
optimization/minimization of immunosuppression to reduce islet toxicity and 
non-adherence to medications; pre-transplant interventions in the donor or 
recipient that enhance islet engraftment and survival; and innovative 
approaches to islet implantation.

2. Improvements in immunotherapy to reduce toxicity, recurrent autoimmunity 
and allograft rejection.  Approaches could include, but are not limited to, 
the following: less toxic immunosuppressive agents; regimens reducing the 
number, dose or duration of immunosuppressive agents; and new and innovative 
therapeutic approaches to induce donor-specific tolerance with or without 
standard immunosuppression, including immunosuppression withdrawal.

3. Interventions to reduce the local complications of the islet 
administration procedure, such as bleeding, thrombosis, and steatohepatitis.  
Approaches could include, but are not limited to, alternate sites of 
administration, improved techniques for islet delivery, and use of 
medications to avert complications. 

In association with clinical trials the CIT will conduct mechanistic studies 
to enhance understanding of rejection, engraftment and/or survival of islets 
in the setting of islet transplantation and their assessment in the clinical 
protocols.  These mechanistic studies are described in detail in RFA DK-04-
005. 

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

1) Study Design, Conduct, Analyses, and Publications  - The DCC will be 
responsible for statistical leadership and for developing innovative clinical 
trial design and analysis methodologies consistent with the consortium 
research agenda; assistance with protocol and manual of operations 
development; developing a data safety and monitoring plan for each protocol 
implemented by the CIT; developing and implementing a plan for adverse event 
reporting, and coordinating this with the activities of the NIAID Regulatory 
Affairs Staff and/or Support Contractor; performing interim analyses of 
safety and efficacy for protocol teams, NIH, and the Data Safety and 
Monitoring Board (DSMB); generating executive summaries of near-final study 
results for use by the protocol team, NIH, and collaborators; conducting 
final analyses and participating on publication writing teams; performing 
cross-protocol or cross study analyses utilizing data from multiple sources 
within and external to the consortium; producing study monitoring reports for 
the consortium and NIH; and conducting analyses and summaries for annual and 
interim reports for NIH-sponsored Investigational New Drug Applications, in 
cooperation with the NIAID Regulatory Support Contractor (see below). 

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

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

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

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

It is expected that the successful applicant will bring a range of 
experiences and perspectives to this consortium that will inform group 
decisions and accelerate the pace of progress toward general clinical 
applicability of islet transplantation for the treatment of T1D. 
Specifically, applicants must have demonstrated capability in providing the 
types of support detailed in 1-5, above, for complex, multi-center trials.  
CIT-DCC applicants should also demonstrate biomedical knowledge relevant to 
cell therapies and T1D, and an understanding of FDA requirements.  These 
skills and expertise should contribute to achieving the following CIT 
objectives.

Study Organization

The CIT will be a consortium of clinical investigators and core support 
facilities. In addition, it will include a Data Coordinating Center (CIT-DCC), 
for which applications are solicited under a separate solicitation (RFA DK-04-
004). A steering committee, (see "Cooperative Agreement Terms and Conditions 
of Award - Collaborative Responsibilities", below), will have responsibility 
for establishing the scientific agenda for the consortium, and for the choice, 
design, planning, execution, and publication of the research studies performed 
by the CIT.  

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

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

MECHANISM OF SUPPORT

This RFA will use the NIH Cooperative Agreement (U01).
 
This RFA is a one-time solicitation.  Future unsolicited, competing-
continuation applications based on this project will compete with all 
investigator-initiated applications and will be reviewed according to the 
customary peer review procedures.  The anticipated award date is September 
30, 2004. The total project period for applications submitted in response to 
this RFA may not exceed five years. At this time, the NIDDK and NIAID have 
not determined whether or how this solicitation will be continued beyond the 
present RFA. 

This RFA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
the investigator is submitting an application with direct costs in each year 
of $250,000 or less, use the modular budget format.  Otherwise follow the 
instructions for non-modular budget research grant applications.  This 
program does not require cost sharing as defined in the current NIH Grants 
Policy Statement at 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.  

The NIH (U01) 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 "Cooperative 
Agreement Terms and Conditions of Award". 

FUNDS AVAILABLE  
 
The NIH intends to commit up to $3 million in total costs in FY 2004 to fund 
one new grant in response to this RFA.  Applicants should request 5 years of 
support.  Because the nature and scope of the research supported by the CIT 
may vary over time and by site, it is anticipated that the sizes of awards 
may also vary.  After initiation of the CIT, awards in subsequent years will 
be determined by the requirements of the specific studies designed by the 
Steering Committee, the level of participation of individual sites, and the 
availability of funds.  Although the financial plans of the NIDDK and NIAID 
provide support for this program, awards pursuant to this RFA are contingent 
upon the availability of funds and the receipt of a sufficient number of 
applications of high scientific merit.  At this time, it is not known if this 
RFA will be reissued.

ELIGIBILE INSTITUTIONS

You may submit an application if your institution has any of the following 
characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments 
o Eligible agencies of the Federal government  
o Domestic (U.S.A) institutions only
o Foreign institutions are not eligible to apply

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with his/her 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 programs.
   
In order to ensure that data analysis is done independently of data 
acquisition, the CIT-DCC cannot have the same Principal Investigator as a CIT-
CC. Within the Consortium an institution may apply for both a CC and the DCC, 
but each must have separate principal investigators and submit a separate 
application with a specific plan of how the independent operation (i.e., 
confidentiality of the study-wide data) of each unit of the CC and DCC will be 
maintained. In addition, there should be no overlap in personnel between the 
CC and DCC.

COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator (PI) as well as the 
institutional official at the time of award.

These 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 part 74 and 92, and other HHS, PHS, and NIH Grant 
Administration policy statements.

The administrative and funding instrument used for this program is the 
cooperative agreement (U01), an "assistance", rather than an "acquisition", 
mechanism, in which substantial NIH scientific and/or programmatic 
involvement with the awardee is anticipated during the performance of the 
activity. Under the cooperative agreement, the NIH purpose is to support 
and/or stimulate the recipient's activity by involvement in and otherwise 
working jointly with the award recipient in a partner role, but it is not to 
assume direction, prime responsibility, or a dominant role in the activity. 
Consistent with this concept, the dominant role and prime responsibility for 
the activity resides with the awardees for the project as a whole, although 
specific tasks and activities in carrying out the research will be shared 
among the awardees and the NIH Scientific Coordinators.

Cooperative agreements are subject to the administrative requirements 
outlined in OMB circulars A-102 and A-110. All pertinent HHS, PHS, and NIH 
grant regulations, policies and procedures, with particular emphasis on PHS 
regulations at 42 CFR Part 52 and HHS regulations at 45 CFR Part 74, are 
applicable. These special terms and conditions pertaining to the scope and 
nature of the interaction between the NIH and the investigators will be 
incorporated in the Notice of Grant Award. However, these terms will be in 
addition to, not in lieu of, the customary programmatic and financial 
negotiations that occur in the administration of cooperative agreements. 
Recipient institutions must agree as a term of award to accept per-patient 
funding for clinical activities. "Start up" costs for clinical research 
resources that must be in place prior to enrollment of subjects may be exempt 
from this requirement, subject to approval by the Steering Committee and the 
NIH Program Directors.

1. Monitoring Clinical Studies

When clinical studies or trials are a component of the research proposed, NIH 
policy requires that studies be monitored commensurate with the degree of 
potential risk to study subjects and the complexity of the study. The NIAID 
policy was published in the NIH Guide on July 8, 2002 and will be used for 
this award.  It is available at: 
http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. 
The full policy, including terms and conditions of award, is available at: 
http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.

This award provides support for one or more NIH-defined Phase III clinical 
trials. The NIH Policy for research supported as an NIH Phase III Clinical 
Trial has been updated in Section III.B. of the "NIH Guidelines on the 
Inclusion of Women and Minorities as Subjects in Clinical Research – Amended, 
October 2001" 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm 
A description of plans to conduct analyses, as appropriate, by sex/gender 
and/or racial/ethnic groups must be included in clinical trial protocols and 
the results of the subset analyses must be reported to NIH in Progress 
Reports, Competitive Renewal Applications, and in the required Final Progress 
Report, as stated in Section III.B. of the Guidelines.

2. Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research 
objectives, approaches and details of the projects within the guidelines of 
the RFA and for performing the scientific activity. Specifically, awardees 
have primary responsibility as described below.

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

The Data Coordinating Center will be involved in collaborations with the NIH 
and the Clinical Centers during all phases of the trial and will maintain or 
contract with the central laboratory used.  The DCC will also coordinate with 
the NIDDK Biosample Repository, if it is available and chosen as the study 
repository for this consortium. If the NIDDK Biosample Repository is not 
available or is not chosen as the sample repository by the NIH at the time the 
study is in the protocol development phase, the DCC will be required to 
maintain or contract with a repository for central storage and distribution of 
serum, tissue, and other samples. Applications must include documentation of 
the ability to acquire human samples and clinical data for the proposed 
studies.  The NIH brochure entitled "Research on Human Specimens: Are You 
Conducting Research Using Human Subjects?" 
(http://www-cdp.ims.nci.nih.gov/policy.html) and OHRP guidance on Repositories, 
Tissue Storage Activities and Data Banks 
http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm 
are available as resources for investigators.  In addition, the DCC will 
coordinate with the NIDDK Data Repository, if it is available, to prepare the 
data for eventual archiving and distribution. Thus, the awardee is expected to 
work cooperatively with Clinical Centers and sponsoring organizations and 
oversee the implementation of and adherence to a common protocol, as well as 
assure quality control of the data collected and storage of collected biologic 
specimens.  In addition to organizing and attending regular meetings 
(including conference calls), the CIT-DCC will be expected to maintain close 
communications with the NIH Scientific Coordinators, and the Principal 
Investigators of the Clinical Centers.
 
Awardees are expected to publish and to publicly release and disseminate 
results, data and other products of the study, concordant with the study 
protocol and governance and the approved plan for making data and materials 
available to the scientific community and the NIH.  Support or other 
involvement of industry or any other third party in any study performed by the 
Consortium -- e.g., participation by the third party; involvement of project 
resources or citing the name of the project or the NIH support; or special 
access to project results, data, findings or resources -- may be advantageous 
and appropriate.  However, except for licensing of patents or copyrights, 
support or involvement of any third party will occur only in the context of a 
Clinical Trials Agreement with the NIH.
 
Upon completion of the project, the DCC is expected to put all study 
intervention materials and procedure manuals into the public domain and/or 
make them available to other investigators, according to the approved plan for 
making data and materials available to the scientific community and the 
NIDDK/NIAID, for the conduct of research at no charge other than the costs of 
reproduction and distribution. Indeed, NIH policy requires that investigators 
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 ; 
Principles and Guidelines for Recipients of NIH Research Grants and Contracts 
on Obtaining and Disseminating Biomedical Research Resources:  Final Notice, 
December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)].  It is 
expected that the specimens and data collected in projects funded by this RFA 
will eventually be made available to the broader scientific community, after 
the proprietary period.

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

The PIs' responsibilities regarding Steering Committee membership, protocol 
development and conduct, and data coordination and management are described 
under Collaborative Responsibilities.

3. NIH Staff Responsibilities

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

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

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

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

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

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

NIH Scientific Coordinator.

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

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

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

Site Support:
NIH Scientific Coordinators or their designates and/or CIT-DCC staff (or 
contractors) will visit all sites prior to patient enrollment, to carry out 
site education with regard to protocol requirements and data submission 
procedures. NIH Scientific Coordinators and DCC staff will meet monthly, by 
teleconference, with the site coordinators for each study, to discuss 
recruitment issues and study operations.  

The NIH Scientific Coordinators will serve as voting members of the Steering 
Committee and will participate in all Committee activities.  

Protocol Development:
As members of the Steering Committee, the NIH Scientific Coordinators will 
serve as a resource with respect to the design of the protocol and will, along 
with the CIT-DCC, assist the Steering Committee in protocol development.

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

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

4. Collaborative Responsibilities

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

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

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

The first meeting of the Steering Committee will be convened by the NIH 
Scientific Coordinators. At this meeting, the group will elect a Chairperson 
from among the Steering Committee members; the NIH Scientific Coordinators and 
the PI of the CIT-DCC are not eligible to be the Steering Committee Chair.  
The Committee will meet in person or by teleconference at least four times 
during the first 12 months of the study and at least twice annually 
thereafter.  Additional meetings by teleconference will be scheduled as 
needed, with need determined by the Steering Committee Chair and the NIH 
Scientific Coordinators. 

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

The Steering Committee or a subcommittee will review the budget and 
expenditures at least once each year at a face-to-face meeting. Clinical 
trials and mechanistic studies will proceed into the implementation stage only 
with the concurrence of both the Steering Committee and the NIH Program 
Directors.  Each Steering Committee member will be expected to participate in 
all Steering Committee activities, e.g., meetings, conference calls, special 
subcommittee activities, etc. as may be necessary.  

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

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

Monitoring Study Progress:
The steering committee, via a Performance Subcommittee, will develop a set of 
criteria for assessing the performance of the participating institutions, 
including institutions participating in consortia arrangements, with 
particular attention to accrual of adequate numbers of eligible patients, 
timely submission and quality of required data and conscientious observance of 
protocol requirements.  These criteria will be the basis for determining 
continued participation.  

The steering committee or a designated sub-committee will prepare an annual 
report containing the following information: progress in ongoing and newly-
initiated clinical trials and mechanistic studies; subject accrual and 
protocol compliance at all participating clinical sites; manuscripts 
published, in press, and in preparation; presentations at regional, national, 
and international meetings; and budget review. The first such report will be 
presented at a joint meeting of the Steering Committee and Mechanistic Studies 
Subcommittee not later than 13 months after the initial notice of award, and 
yearly thereafter.  The CIT-DCC will take the lead in writing this report; the 
NIH Scientific Coordinators will not participate substantively in the 
development or submission of the annual report, and will serve as the primary 
NIH staff members responsible for review of the report by the sponsoring 
agency.

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

Performance Subcommittee:
The performance subcommittee will develop a set of performance criteria to 
evaluate accrual, data submission, and compliance at each participating 
institution in the consortium, including institutions participating in 
consortium arrangements.  These criteria, after approval by the Steering 
Committee, will form the basis for determining continued participation of each 
site in the consortium, on a yearly basis.

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

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

Publication and Presentation of Study Findings:
Timely publication of major findings is encouraged.  Publications and oral 
presentations of work performed under this agreement will require appropriate 
acknowledgment of the participating institutions and NIH support.  Policies 
for directing analyses of aggregate and site-specific data will be developed 
by the Steering Committee. Review and approval by the Steering Committee will 
be required for all analyses prior to publication or presentation according to 
criteria that will be developed by the Steering Committee. The Steering 
Committee may establish a Publications and Presentations Subcommittee to carry 
out this function.

5. Arbitration

Any disagreement that may arise on scientific or programmatic matters (within 
the scope of the award) between award recipients and the NIH may be brought 
to arbitration. An arbitration panel will be composed of three members -- one 
selected by the Steering Committee or by the individual awardee in the event 
of an individual disagreement, a second member selected by the NIH, and the 
third member with expertise in the relevant area and selected by the two 
prior members will be formed to review any scientific or programmatic issue 
that is significantly restricting progress. While the decisions of the 
Arbitration Panel are binding, these special arbitration procedures will in 
no way affect the awardee's right to appeal an adverse action in accordance 
with PHS regulations at 42 CFR Part 50, subpart D, and HHS regulations at 45 
CFR Part 16.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA 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:

o Direct questions about scientific/research issues to:

Thomas L. Eggerman, M.D., PhD
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 697
Bethesda, MD  20892-5460
Telephone:  (301) 594-8813
FAX:  (301) 480-3503
Email:  te39q@nih.gov

Nancy D. Bridges, M.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Disease
6610 Rockledge Drive, Room 3039
Bethesda, MD 20892-6603
Telephone: (301) 451-4406
FAX: (301) 480-3503
Email: nb143s@nih.gov 

Questions may also be submitted to the email address 
clinislettransplant@extra.niddk.nih.gov where they will be answered by email.  
In addition, these questions and answers will be posted at the NIDDK website 
http://www.niddk.nih.gov/fund/diabetesspecialfunds/CIT/ which links to 
frequently asked questions that prospective applicants have submitted. 
Applicants are strongly encouraged to visit this website on a regular basis in 
the course of preparing their applications.

o Direct questions about peer review issues to: 

Francisco O. Calvo, PhD 
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 653 
Bethesda, MD 20892-5452
Telephone:  (301) 594-8885
FAX:  (301) 480-3505
Email: fc15y@nih.gov  
 
o Direct questions about financial or grants management matters to:

Mary K. Rosenberg
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 708 
Bethesda, MD 20892-5452 
Telephone:  (301) 594-8891 
FAX:  (301) 594-9532
Email: mr239s@nih.gov   

Ann White-Devine
Division of Extramural Activities
National Institute of Allergy and Infectious Disease
6700B Rockledge Drive, Room 2118
Bethesda, MD  20892-7614
Telephone: (301) 402-5601
FAX: (301) 480-3780
Email: ad22x@nih.gov

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

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

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:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 653
Bethesda, MD  20892-5452
(for express/courier service:  Bethesda, MD  20817)
Telephone:  (301) 594-8885
FAX:   (301) 480-3505

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form.  The PHS 
398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

SUPPLEMENTARY INSTRUCTIONS

1. Applications may be submitted by a single center or by a consortium of 
centers. 

2. The applicant for a CIT-DCC must demonstrate experience and ability in 
coordinating multi-center clinical trials in all phases, consistent with the 
objectives and scope described above, including: protocol and manual of 
operations development, staff training in study procedures, research 
instrument development, data collection and management, quality assurance, 
data analysis, distributed data entry, electronic communications, 
administrative management and coordination. Specific experience in 
coordinating or monitoring studies of diabetes and/or surgical procedures is 
not required, but the applicant may wish to include an investigator with this 
expertise in the application as a collaborator or advisor.

3. The CIT-DCC application must propose a research plan that includes the 
structure of a database and an information core that they believe should be 
collected on all participants that are prospectively enrolled. 

4. CIT-DCC Applications must provide evidence the applicant's expertise and 
experience in biostatistics, clinical study design and protocol development. 
Specific examples of prior or ongoing successful collaborations with clinical 
investigators in the design and implementation of multicenter studies should 
be included, with reference to the applicant's role in establishing 
eligibility criteria, baseline and outcome measures, methods of randomization, 
sample size and power calculations, and methods and frequency of data 
collection and entry. In addition, experience with monitoring accuracy of data 
collection, quality control procedures including training and certification 
for multiple protocols, some of which may occur simultaneously, and managing 
labeling and handling of serum and tissue samples (see below) should be 
described. The CIT-DCC application must also describe the applicant's 
expertise and experience in the development of Data Safety and Monitoring 
Plans (DSMP) and administrative support of Data and Safety Monitoring Boards 
(DSMB).  The CIT-DCC application should also document expertise and experience 
with Institutional Review Board (IRB) and the United States Food and Drug 
Administration (FDA) approval processes.  

5. The applicant for the DCC must provide a plan for handling of laboratory 
specimens.  NIDDK and NIAID anticipate that some clinical outcome measures 
may be centrally assessed.  Laboratories responsible to the CIT-DCC will 
manage specimens and laboratory studies as required by the Steering 
Committee. Applications must include documentation of the ability to acquire 
human samples and clinical data for the proposed studies.  The NIH brochure 
entitled "Research on Human Specimens: Are You Conducting Research Using 
Human Subjects?" (http://www-cdp.ims.nci.nih.gov/policy.html) and OHRP 
guidance on Repositories, Tissue Storage Activities and Data Banks 
http://www.hhs.gov/ohrp/humansubjects/guidance/reposit.htm are available as resources for 
investigators.

6. The application must reflect adequate time commitment of personnel. Levels 
of effort that are awarded will vary depending on the requirements of the 
studies to be performed and anticipated contributions to the CIT.  

7. The CIT will be a collaborative effort that will require frequent 
interactions of awardees among themselves and with the NIH. Applicants must 
explicitly indicate their willingness to: participate in Steering Committee 
meetings (expected to occur approximately 4 times during the first year and 2 
times per year in subsequent years, in or near Bethesda, MD), site visits 
required by the NIH, and regular telephone conference calls; cooperate with 
other awardees in the development and design of research protocols; abide by 
common definitions, common methods for patient selection and enrollment, and 
common protocols, procedures, tests,  as chosen by majority vote of the 
Steering Committee; comply with data reporting procedures and timelines as 
established by the Steering committee and the DCC;  comply with study policies 
and quality assurance measures approved by the Steering Committee; agree to 
oversight of the study by a Data and Safety Monitoring Board (DSMB); report 
all adverse events in accordance with procedures established by the Steering 
Committee 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, and accept the Cooperative Agreement Terms and 
Conditions of Award given below.
 
8. Applicants should state in their application their willingness to 
participate in collection of biologic samples as well as clinical data that 
may be used for future studies related to the treatment of T1D by 
investigators both inside and outside of the CIT. This RFA has a special 
requirement that applicants acknowledge in a "Sharing Plan" in the proposal 
that they will share the specimens and data collected with the wider 
scientific community, through eventual transfer of these materials to the 
NIDDK Central Biosample and Data Repositories or through another mechanism 
determined by NIH.  A data sharing plan as approved, after negotiation with 
the applicant when necessary, will be a condition of the award.  Evaluation of 
the Non-competing Grant Progress Report (PHS 2590) will include assessment of 
the effectiveness of research resource release.

9. Budget Information: The actual award will vary yearly, depending upon the 
number and character of studies developed and implemented by the CIT. However, 
applicants for the CIT-DCC must prepare estimated budgets for five 12-month 
periods, not to exceed $3 million total cost per year. The budget must address 
all of the DCC responsibilities outlined in other sections of this RFA.  In 
particular, the budget should reflect the expectation that the clinical trials 
will require training, monitoring, and auditing for GCP and GTP at three to 
five sites for each protocol. They should reflect the assumption that the 
consortium will initiate 2 protocols in the first year, and up to 4 protocols 
per year in years 2 through 4; each of these protocols is expected to be 
completed over a course of 2 to 4 years. Thus, several protocols will be 
running concurrently, in different phases (development, implementation, 
analysis, or writing).  The budget must also include costs of the following: 
developing, maintaining, and entering data into the database; administrative 
support of the Data and Safety Monitoring Board (including twice yearly face-
to-face meetings and twice yearly telephone calls); face-to-face steering 
committee meetings (exclusive of travel and per diem for CC investigators) up 
to four times during the first year and two times/year in subsequent years in 
or near Bethesda, MD; telephone conference calls of the executive committee 
and subcommittees, and with NIH program staff; shipping and analysis of serum 
and tissue specimens sent to Central Laboratory(s), as well as shipment and 
storage of other samples in a repository, which may be administered through a 
subcontract from the CIT-DCC or through the NIDDK Biosample Repository. While 
the actual award may vary, the CIT-DCC may estimate $600,000 total costs/year 
for consortium/contractual agreements with a central laboratory(s) and/or 
sample and data repositories, including costs of shipping, and/or for the 
purchase and distribution of study drugs. 

10. The applicant must provide a plan for sharing of research data for use by 
other researchers (See Terms and Conditions of Award). For guidance, the 
applicant is referred to The Final NIH Statement on Sharing Research Data, at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form 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/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: 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
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all 
appendices must be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752 
Bethesda, MD  20892
(Courier use ZIP 20817)

APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  If an application is received 
after that date, it will be returned to the applicant without review.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA 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 an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA 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. 

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK and NIAID.  Incomplete applications will not be 
reviewed.

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 
the NIDDK in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will:

o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score.
o Receive a written critique
o Receive a second level review by the National Diabetes and Digestive and 
Kidney Disease Advisory Council.
 
REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application's overall score, weighting them as appropriate for each 
application.

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
   
The 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 be advanced? What 
will be the effect of these studies on the concepts or methods that drive 
this field?

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

INNOVATION: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?

INVESTIGATOR: Is the investigator 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 (if any)?

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success? Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements? Is there evidence of institutional support?  

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

Documentation of experience and ability in all aspects of multi-center 
clinical trials, including protocol and manual of operations development, 
staff training, research instrument development, data collection and 
management, quality assurance, biostatistical expertise as applied to study 
design, randomization, and data analysis, administration and coordination, 
and human subjects protection.

Documentation of experience and expertise in development of safety monitoring 
plans, including considerations for "stopping rules", administrative support 
of a DSMB, and interactions with site IRBs.

Adequacy of the proposed research database design, data entry methods, and 
subject information core.

Documentation of experience and ability in the handling of laboratory 
specimens in multi-center clinical studies.

Documentation of experience and expertise in FDA regulatory requirements 
pertaining to IND applications and Good Tissue Practice compliance, and with 
auditing of production and testing records for manufacture of cellular 
products. 

Description of personnel and facilities adequate to implement the proposal, 
including personnel time commitment.

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 criteria included in the 
section on Federal Citations, below)
 
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.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 
below).

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 
398 research grant application instructions (rev. 5/2001) will be assessed.  

SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct 
costs in any year of the proposed research are expected to include a data 
sharing plan in their application. 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 priority score. (See 
instructions and URL to policy in the Federal Citations, below.)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:          March 16, 2004      
Application Receipt Date:               April 13, 2004          
Peer Review Date:                       July, 2004                   
Council Review:                         September, 2004  
Earliest Anticipated Start Date:        September 30, 2004 

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Programmatic priorities.

REQUIRED FEDERAL CITATIONS 

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). The establishment of data 
and safety monitoring boards (DSMB's) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants. (NIH Policy for Data Safety and Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking more than $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, 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.

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 AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are 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 RESEARCH INVOLVING HUMAN SUBJECTS 
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

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 that is available at 
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 proposals for research involving human 
subjects.  This policy announcement is in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, 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 (see 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. 

PUBLIC 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 public 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 RFA 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.

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). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

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. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to 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 
RFA 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 Catalogue of Federal Domestic Assistance at 
http://www.cfda.gov/ in the following citations: No. 93.847, Diabetes 
Research, No. 93.855, Immunology, Allergy, and Transplantation Research and 
No. 93.856, Microbiology and Infectious Diseases Research. Awards are made 
under authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and administered under NIH grants policies 
and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is 
not subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.

The NIH Grants Policy Statement is available at 
http://grants.nih.gov/grants/policy/policy.htm. This document includes 
general information about the grant application and review process; 
information on the terms and conditions that apply to NIH Grants and 
cooperative agreements; and a listing of pertinent offices and officials at 
the NIH.  All awards are subject to the terms and conditions, cost 
principles, and other considerations described in the NIH Grants Policy 
Statement. 

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.


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H H S Department of Health
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