HUMAN PANCREATIC ISLET CELL RESOURCES (ICRs)

Release Date:  January 3, 2001

RFA:  RFA-RR-01-002 (This PA has been modified, see RFA-RR-05-003)

National Center for Research Resources
 (http://www.ncrr.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)
Juvenile Diabetes Research Foundation International
 (http://www.jdf.org)

Letter of Intent Receipt Date:  February 8, 2001
Application Receipt Date:       March 21, 2001

PURPOSE

Recent publications reported that some patients with Type I diabetes 
mellitus have achieved long-term independence from exogenous insulin 
after receiving human pancreatic islet cell transplants.  To expand 
this observation and, ultimately, bring such therapies into practice, 
the National Center for Research Resources (NCRR) together with the 
National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK) and the Juvenile Diabetes Research Foundation International 
(JDRFI) invites applications from institutions to establish Islet Cell 
Resources (ICRs) for the isolation, purification, characterization of 
human pancreatic islet cells for transplantation into diabetic 
patients.  In addition, this Request for Applications (RFA) will 
establish a separate Administrative and Bioinformatics Coordinating 
Center (ABCC) to coordinate the ICRs’ activities.

Establishment of up to six ICRs in a wide geographic distribution 
across the United States is planned.  These centers would be 
responsible for the procurement of whole pancreata, isolation and 
quality control of islet cell preparations, and distribution of islets 
for approved research or clinical protocols.   They would also perform 
research and development to improve isolation techniques, cellular 
viability and function, and shipping procedures.

Organizations whose applications receive a favorable initial review 
will be evaluated, subsequently, for compliance with the Food and Drug 
Administration (FDA) Good Manufacturing Practice (GMP) guidelines 
relevant to Phase I cell therapy trials.   This entails that each ICR 
successfully complete a site visit performed by an outside team of 
inspectors who qualified to evaluate such compliance.  This evaluation 
will be a condition of grant award.

ABCC applicants will compete separately under this RFA to coordinate 
ICRs’ activities, organize their meetings, and correlate data that 
reflect the efficacy of both the methods used to prepare islets and the 
assays to predict functionality and clinical outcome. The ABCC will 
also manage the relevant laboratory and clinical data generated through 
the activities of the ICRs .  While the ABCC may be located within the 
same institution as one of the selected ICRs, the director of the ABCC 
must remain independent of that ICR and any other ICR to both preserve 
the integrity of the studies and avoid any perceived or real conflict 
of interest. 

ELIGIBILITY REQUIREMENTS

Applications for the ICR portion of this RFA may be submitted by 
domestic not-for-profit organizations, public and private 
organizations, such as universities, colleges, hospitals, laboratories, 
units of state and local governments, and eligible agencies of the 
Federal government.  Foreign institutions are not eligible to receive 
awards under this solicitation.  However, under exceptional 
circumstances, a foreign component critical to an ICR may be included 
as a part of the program.  

Applications for the ABCC portion of this RFA may be submitted by 
domestic for-profit and not-for-profit organizations, public and 
private organizations, such as universities, colleges, hospitals, 
laboratories, units of state and local governments, and eligible 
agencies of the Federal government.  Foreign institutions are not 
eligible to receive awards under this solicitation.  

Individual members of racial and/or ethnic minority groups, women, and 
persons with disabilities are encouraged to apply as principal 
investigators.  All current policies and requirements that govern the 
research grant programs of the National Institutes of Health (NIH) will 
apply to grants awarded under this RFA.  

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program 
will be the cooperative agreement (U42), an assistance mechanism rather 
than an acquisition mechanism, in which substantial NIH scientific 
and/or programmatic involvement with the awardees is anticipated during 
performance of the activity.  Under a cooperative agreement, the NIH 
supports and/or stimulates the recipients’ activities by working in 
partnership with the awardee, without assuming the direction of, prime 
responsibility for, or dominance in the activities.  Responsibilities 
for the project as a whole reside with the awardees, although specific 
tasks and activities are shared among the awardees and the NIH 
Institutes and Centers (ICs). Details of the responsibilities, 
relationships, and governance of studies funded under a cooperative 
agreement are discussed later in this document under the section 
entitled “Terms and Conditions of the Award.”  

The anticipated award date is September 2001.  The total project period 
for an application submitted in response to this RFA may not exceed 
five years. Although this RFA is currently anticipated to be a one-time 
solicitation, if it is determined that there is a sufficient, 
continuing need, NCRR will invite competitive new and/or competitive 
continuation cooperative agreement applications for review in accord 
with the procedures described in REVIEW CONSIDERATIONS.  

FUNDS AVAILABLE

Up to six awards for ICRs and one award for an ABCC will be made under 
this RFA.   Over their five-year duration, the awards made to these 
ICRs would reach a total of up to ~$11million (direct costs) while the 
total award to the single ABCC would be up to $3.5 million (direct 
costs) to support their infrastructure .   The NIDDK and JDRFI will 
provide additional financial support based on the number of islet cell 
preparations made annually by each of the awardees.  Because the nature 
and scope of the efforts proposed in response to this RFA may vary, it 
is anticipated that the size of an award will vary between ICRs in all 
years.  

Although the financial plans of the NCRR, NIDDK and JDRFI (hereafter 
termed Funding Entities) 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 appropriate 
scientific and technical merit.  Designated funding levels are subject 
to change at any time prior to final award, due to unforeseen 
budgetary, administrative, or scientific developments.  It is not known 
if new or competing renewal applications will be accepted or if this 
RFA will be reissued.

RESEARCH OBJECTIVES

Background

Diabetes mellitus affects approximately 16 million people in the United 
States.  Individuals with Type I diabetes have lost their ability to 
manufacture sufficient amounts of insulin due to autoimmune destruction 
of the insulin-producing beta cells that are grouped with other types 
of secretory cells within the “islets of Langerhans” of the pancreas.

While injection of exogenous insulin has long been the standard 
treatment for patients with Type I diabetes, transplantation of human 
islet cells may be an alternative.  However, the recovery of functional 
pancreatic islets is a complex procedure and needs to be optimized.  
Several aspects of the process may be critical: the clinical status of 
the donor before removal of the pancreas, surgical procedures involved 
in its excision, the enzymatic dispersal of the pancreatic components, 
the transplantation procedure and the recipient’s immunosuppression 
remain to be optimized. 

Selection of appropriate recipients for islet transplantation requires 
characterization of the target population with particular attention to 
their response to insulin therapy.  Reports from the Diabetes Control 
and Complications Trial (DCCT) suggest that intensive treatment 
regimens that achieve tight control of blood glucose can significantly 
reduce the onset and progression of resultant complications in 
individuals with Type I diabetes.  However, some diabetic patients 
practicing tight control experience lability of blood glucose levels in 
response to changes in health status, diet, exercise, or insulin dose. 
Because even small changes in their daily regimen may interfere with 
glucose control, these diabetic patients are said to be "brittle".  For 
this subpopulation, insulin therapy is life saving, but may lead to 
frequent adverse events such as severe hypoglycemia. Islet cell 
transplantation could provide significant benefits to brittle diabetics 
for whom effective regulation by insulin therapy is difficult. 

Objectives and Scope

The objectives of this RFA are to 1) establish ICRs to optimize the 
isolation procedures to obtain high yields of functional islet cells 
and to provide well-characterized islet cells for transplantation into 
type 1 diabetic patients, 2) distribute islet cells to investigators 
for clinical or basic research, and 3) develop isolation procedures 
that result in maximal islet cell function upon transplantation.

ICR applicants should describe plans to establish collaborations with 
clinical programs that have experience in transplanting human islet 
cells and wish to optimize such protocols. 

The ICR research plan should include proposals to: 1) create and/or 
participate in a network of ICRs to recruit and evaluate pancreas 
donors, 2) obtain human pancreata; 3) distribute islets to both 
clinical and basic science researchers; 4) ensure quality control of 
islet cell isolation and provide a scientific basis for their use in 
transplantation or basic research; 5) determine the physiologic and 
genomic components that are correlated with longevity, function and 
portability of pancreatic islets; 6) facilitate approved 
transplantation protocols and correlate consequent clinical responses 
with characteristics of the islets provided.
 
The ABCC will 1) be responsible for the organization and conduct of 
Steering Committee meetings whose agendas would include protocol review 
and evaluation of progress; 2) collect data, organize and analyze the 
methods and assays used to produce islet cells and correlate these data 
with post-transplant islet cell function; 3) correlate clinical trial 
data such as patient and donor demographics and baseline assessments, 
and relevant laboratory and clinical data that result from the use of 
the islets generated.  The ABCC will maintain the database into which 
all ICRs and collaborating institutions will deposit their data for 
subsequent analysis.  Respondents to the ABCC portion of this RFA 
should also address issues such as data storage, archiving, retrieval, 
analysis and data mining, quality control issues, security, and 
information transfer in the application.

The research plan should follow the instructions in the PHS 398 
application form (rev. 4/98, http://grants.nih.gov/grants/forms.htm).

Program Structure

Each ICR should be an identifiable organizational unit formed either 
within a single institution or with a collaborating institution.  The 
expertise and technologies relevant to this RFA should reside within 
the ICR, providing a multidisciplinary structure that can coordinate 
activities between basic science investigators and clinicians to 
translate basic research discoveries into clinical applications.  The 
ICR will facilitate research by providing laboratory-based and clinical 
investigators with access to technology and equipment needed for islet 
cell research that leads to implementation of practical transplantation 
protocols.  These may include current Good Manufacturing Practice 
(cGMP) suites, Good Laboratory Practice (GLP) isolation procedures, 
microarray technology, and cell sorters.  Applicants must have 
demonstrated significant research expertise in islet cell 
transplantation and have facilities within its institution that would 
enhance its productivity.  While each ICR may not have a Training 
Program specifically designed to advance islet cell transplantation 
therapy, the institution may wish to use this opportunity to educate 
other investigators about relevant scientific and ethical issues.  

The ABCC will serve the administrative functions common to the ICRs, 
house the bioinformatics core, maintain the consolidated database, 
provide administrative oversight of the Steering Committee and 
coordinate ICR activities such as complex assays and unique 
technologies that would best be housed in a generally accessible, 
single core.  While an institution may apply for both the ABCC and ICR 
cooperative agreements, applications for the ABCC award should be 
submitted separately from that of the ICR to enable each to be judged 
on its own merits.  If a single institution does apply for both 
agreements, the independence of the ABCC from the ICR must be clearly 
described in a manner that documents the absence of a conflict of 
interest.  An application for the ABCC award should include a plan that 
describes its proposed function, its resources and how it would 
facilitate ICR interactions.  

A Steering Committee will be responsible for scientific oversight and 
development of collaborative interactions among the ICRs, an example of 
such being shared research on islet cell isolation procedures. 

A representative and an alternate from each ICR must be designated to 
serve on the Steering Committee and must recuse themselves from 
discussion of any application submitted by individuals affiliated with 
their home institution.  

Each ICR must agree to provide pancreatic islets only to investigators 
whose protocols, either basic or clinical, have received favorable 
review by the Steering Committee and comply with the current goals of 
the Funding Entities.    

Applicants are strongly encouraged to identify a clinical research 
facility within their institution to facilitate islet cell 
transplantation.  The clinical facility personnel should help to 
maintain quality assurance and compliance of the various aspects of the 
protocols.  

Specialized Resource Facilities and Services

Advanced resources are required to develop pre-clinical data and 
implement clinical studies on cell therapies. Applicants should 
document the availability of existing laboratories, unique assays, and 
cell preparation facilities.  Clinical activities, either within the 
applicant’s own institution or collaborating institution, that would to 
assist the awardee in achieving the goals outlined within this RFA 
should also be described.

Each ICR application must include a description of all the proposed 
core components of the types cited above, and how they would relate to 
the ICR and other awardees.  For those applications that are in the 
funding range, a committee of representatives from the Funding Entities 
will determine which will be selected as common cores to avoid 
unnecessary duplication of effort among all the ICRs.  NIH-supported 
investigators from both within and outside of the ICRs would be 
eligible to submit a request for a service that any of the ICR cores 
provide.  The Steering Committee would review the requests based on 
their scientific merit.  Subsequently, the Funding Entities would 
consider these requests with regard to the scientific review, program 
relevance and availability of funds and set priorities based on these 
factors.  Funds would be awarded to the core facility to offset the 
cost of these common services.

An ICR application should, at minimum, address:

o Experience of key personnel
o Pre-clinical research experience
o Clinical research experience and collaborations in islet cell 
transplantation 
o Core resources and plans for sharing these resources among ICRs
o Human Subjects issues
o Data Safety Monitoring Plan
o Steering Committee function
o Interaction with the ABCC

An ABCC application should, at minimum, address:

o Experience of key personnel
o Experience in coordinating multi-center research programs
o Biostatistical and bioinformatics experience and plans 
o Existing computer facilities
o Coordination of core resources among ICRs
o Human Subjects issues
o Data Safety Monitoring Plan
o Proposed Steering Committee function
o Interaction with the ICRs

SPECIAL REQUIREMENTS

The cooperative agreement (U42) will require collaboration among the 
NCRR Program Coordinator, the NIDDK Program Officer, the JDRFI 
Representative, and the Directors of each ICR in order to assure 
efficiency and progress toward the stated goals of this RFA.   Plans to 
develop these synergistic relationships should be addressed in each 
application.  The following terms and conditions will be incorporated 
into the award statement and provided to the ICR Director as well as 
the institutional official at the time of award.

Terms and Conditions of Award

These special Terms and Conditions 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, and other 
HHS, PHS, and NIH Grant Administration policy statements.

1.  Awardee Rights and Responsibilities

Each ICR Director will plan and detail the functions of the requisite 
laboratories and cell isolation facilities and retain primary 
responsibility for the performance of these activities.  The Directors 
and associates must agree to participate as members of the ICR Steering 
Committee.  The ICR Directors will recommend outside experts to balance 
the composition and size of the Steering Committee to both provide 
requisite expertise and guarantee that the entire number of NIH 
representatives does not exceed 40 percent of the total membership.  
Each member, including the outside experts, will have one vote on 
matters discussed at the Steering Committee meeting.

The ABCC Director and the ICR Directors, in cooperation with the other 
Steering Committee members, will be responsible for developing the 
details of the ICR operating policies and documents, including the 
definition of objectives, protocols, implementation, and interaction to 
establish a clinical islet cell resource program that is responsive, 
efficient, and ethical. 

The ABCC Director will assist the Chairperson of the ICR Steering 
Committee in organizing Steering Committee meetings.  The ABCC will be 
responsible for administrative matters related to Steering Committee 
meetings, including preparing agendas, writing and distributing 
minutes, communicating with outside investigators and the lay public 
and receiving applications for ICR services from investigators.

In addition, the ABCC will maintain close contact with the ICRs, the 
NCRR Program Coordinator, NIDDK Program Officer and JDRFI 
representative.   It will assist in coordinating the research programs 
and core resources among the ICRs, provide biostatistical and 
bioinformatics support to the ICRs, maintain current and relevant 
databases, arrange appropriate advertising and publicity for the ICRs 
upon approval by the Steering Committee and prepare a comprehensive 
annual report for the program in a timely fashion.  

The Funding Entities will establish rules governing the selection and 
tenure of the Chairperson and any outside experts for the Steering 
Committee.  The Chairperson of the Steering Committee, the ABCC 
Director and each ICR Director must present updates of their activities 
at each meeting that will be held either by telephone conference call 
or in the metropolitan Washington D.C. area.  The ABCC will be 
responsible for all administrative aspects of the Steering Committee 
meetings.  Individual ICR Directors and the ABCC Director will be 
responsible for submission of their Annual Progress Reports and other 
reports to NCRR in compliance with NIH and other Federal Guidelines.

2.  I/C Staff Responsibilities

One Health Scientist Administrator from the NCRR will be designated to 
serve as the NCRR Program Coordinator of this cooperative agreement. 
This individual will assist in coordinating the activities of the 
awardees and in facilitating exchange of information between them and 
the Funding Entities.

The NCRR Program Coordinator, one Program Officer from NIDDK and one 
representative from JDRFI will serve on the Steering Committee.  NCRR, 
NIDDK and JDRFI will also designate individuals who will serve as their 
respective alternates to the Steering Committee.  In consultation with 
the awardees, these individuals and their alternates may convene 
workshops or sponsor seminars within existing meetings to update the 
Directors on advances in cell transplantation and immune modulation.  

As members of the Steering Committee, the NCRR Program Coordinator and 
NIDDK Program Officer and JDRFI Representative participate in all 
meetings and assist in developing operating policies and procedures but 
do not to direct the activities of the ICRs.  They also serve as 
liaisons between the Steering Committee and the NIH and as information 
resources on research activities in cell transplantation and diabetes 
mellitus and may further facilitate activities by organizing meetings 
of groups having specific expertise in areas that could augment the 
research activities described in this RFA.  

NCRR and NIDDK reserve the right to terminate or modify each ICR award 
in the event of (a) failure to develop, implement or maintain mutually 
acceptable basic and clinical research protocols, (b) substantial 
shortfall in efficiency, data reporting, quality control, or other such 
major breach in islet cell production, laboratory studies or clinical 
protocols, (c) substantive changes in an agreed-upon protocol with 
which the Funding Entities cannot concur, (d) ethical issues, (e) lack 
of compliance with FDA GMP guidelines 18 months after issuance of the 
initial Notice of Grant Award or (f) significant non-compliance with 
other relevant Federal guidelines.

3.  Collaborative Responsibilities

The Steering Committee coordinates and facilitates the activities 
supported by this cooperative agreement. 
 
The members of the Steering Committee will establish the policies and 
operating procedures of both itself and the ICRs and will be described 
within a Policy and Procedure Document. The Document will also detail 
requirements for basic and clinical research protocols to use ICR-
generated islets including quality control, quality assurance, testing 
procedures, human subjects protection, conflict of interest, and 
intellectual property and regulatory issues as they evolve throughout 
the duration of the studies.  The Steering Committee will also make 
provisions for an arbitration panel as described below.  Criteria for 
accession and discontinuance of use of the ICR facility will also be 
delineated. The Director of each Funding Entity will review and must 
approve these ICR guidelines prior to their implementation.

The Steering Committee will meet three times during the first year of 
the awards and semi-annually, thereafter.  ICR Directors are also 
responsible for formulating consistent policies for dealing with 
recurring situations that require coordinated action at Steering 
Committee meetings.  

Data and Safety Monitoring Board

All clinical protocols supported by ICR resources must engage a Data 
and Safety Monitoring Board (DSMB), which will provide overall 
monitoring of interim data and safety issues.  The DSMBs should be 
assembled by the institutions or funding organizations that sponsor 
those clinical protocols.  The ICRs will not develop an independent 
DSMB but should present a data safety monitoring plan in their 
applications.

Intellectual Property

The Bayh-Dole Act is implemented through Department of Commerce 
regulations 37 CFR 401.  These regulations define terms, parties, 
responsibilities, prescribe the order of disposition of rights, 
prescribe a chronology of reporting requirements, and delineate the 
basis for and extent of government actions to retain rights.   The 
patent rights clauses are found at 37 CFR Part 401.14 and are 
accessible from the Interagency Edison web page, www.iedison.gov .  ICR 
awardees will have primary rights to their data developed under these 
awards, subject to Government rights of access consistent with current 
Federal policies.  

Database

Information developed as a result of ICR activities will be held in a 
central database by the ABCC.  Such data, which will include, for 
example, laboratory procedures, methods of data analysis and reports, 
will be made available to the ICR Directors, NCRR Program Coordinator, 
NIDDK Program Officer and JDRFI Representative.  The database will not 
be distributed to the public until the relevant studies have been 
completed and only with the concurrence of the Steering Committee.  The 
database must be designed to protect patient identity and ensure the 
privacy of their medical and genetic data.

Publication

Awardees are encouraged to publish and to publicly release and 
disseminate results, data and other information developed by this 
cooperative agreement.  Such documents, written by an individual ICR or 
by a consortium of ICRs, may be published only after approval by the 
Steering Committee.  However, during or within three years beyond the 
end date of the project support period, unpublished data, unpublished 
results, data sets not previously released, or other study materials or 
products are to be made available to any third party only with the 
approval of the Funding Entities and in accordance with the 
stipulations within this document.

Arbitration

Any disagreement that may arise between award recipients and the 
Funding Entities on scientific or programmatic matters may be brought 
to arbitration.  A panel of external consultants will be created, and 
convened as needed, to resolve any irreconcilable differences of 
opinion related to such matters.  The panel will include one member 
selected by the ICR Directors, one member selected by the Funding 
Entities, and a third member chosen by the other two members of the 
arbitration panel.  These special arbitration procedures in no way 
affect an awardee's right to appeal an adverse determination in 
accordance with PHS regulations at 42 CFR part 50, subpart D and HHS 
regulations at 45 CFR part 16.  Applicants should anticipate probable 
areas of conflict and put forward an arbitration plan in their 
applications.

LETTERS OF INTENT

Prospective applicants are asked to submit a letter of intent that 
includes a descriptive title of the proposed application, the name, 
address, and telephone number of the Principal Investigator, the 
identities of other key personnel and participating institutions, and 
the number and title of the RFA in response to which the application 
may be submitted.  Although a letter of intent is neither required nor 
binding, and does not enter into the review of a subsequent 
application, its contents allow NCRR staff to estimate the potential 
review workload and plan the review.
The letter of intent is to be faxed, e-mailed, or mailed to John Meyer, 
Ph.D. at the address listed under INQUIRIES by February 8, 2001.

APPLICATION PROCEDURES

The research grant application form 398 (rev. 4/98) is to be used in 
applying for the cooperative agreement described in this RFA. These 
forms are available at most institutional offices of sponsored research 
and from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, Two Rockledge Centre, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, 
email: grantsinfo@nih.gov.  Application kits are also available on the 
Internet at:  http://grants.nih.gov/grants/funding/phs398/forms_toc.html


An applicant may apply for designation as either an ICR or the ABCC.  
If an institution wishes to apply for both an ICR and ABCC award, 
separate applications must be submitted for each with special attention 
to the issues of conflict of interest described below.

Material to Include in the ICR Application

An application to establish an ICR should be submitted by the proposed 
Director who will be responsible for organizing and maintaining the ICR 
research program.  A clear description of the plans for communication, 
interaction, collaboration and sharing among investigators within and 
between each ICR should be included.  Each proposed ICR Director should 
also propose procedures for handling day-to-day issues, both 
administrative and scientific. The ICR Director should have the 
responsibility for oversight and coordination of all projects or 
components involving that ICR, whether or not they occur at his/her 
institution.  Support for at least 0.25 FTE will be provided for the 
position of ICR Director.  Provision will be made for partial support 
for a qualified investigator(s) to assist in the direction of the ICR 
and additional support for individuals to perform technical procedures. 
The application should detail how this would be accomplished through 
the inclusion of diabetologists, transplant surgeons and immunologists 
who are active in clinical research. 

The ICR application should provide and justify an estimate of the cost 
of producing islets cell per transplant recipient and per basic 
research protocol.

In addition, each ICR must describe any clinical core either at its own 
institution or collaborating institution that would participate with 
the ICR in islet cell transplant projects.  Each application must also 
describe the institutional oversight procedures to be employed and must 
clearly outline the proposed administrative and organizational 
structure of their ICR, including integration, collaborative 
arrangements, and roles for key investigators from all institutions 
involved with the ICR. The applicant must also state willingness to 
participate in the Steering Committee that will integrate the 
activities of the ICRs and agree to abide by its governance.

Description of Proposed Resources

Applicants to this RFA should consider the points below as examples of 
relevant information to include in the application.  These are examples 
only and should not be construed as being required or limiting. 
Applicants are encouraged to address these and/or other points 
pertinent to the objectives of the RFA.

ICR

Harvesting

o Describe the existing physical facility for isolation and assay of 
islet cells and the operational guidelines under which GLP is assured 
and islet cells are produced under cGMP conditions.

o Describe plans for procurement of pancreata, including any relevant 
contracts and consortia agreements.  Estimate the number of pancreata 
available to the proposed ICR annually for islet isolation.  This would 
include all sources, including local transplantation networks.  The 
basis upon which this estimate is made should be documented and 
presented and accompanied by letters of agreement from the 
organizations and institutions that will provide pancreata to the ICR.  
If transplantation of whole pancreas is performed at the applicant's 
institution, cite the number of whole pancreata that have been 
transplanted annually for the past five years.  Describe the rationale 
employed when deciding whether the providing organization will allocate 
a pancreas to either a whole organ transplantation or islet cell 
transplantation protocol.

o Recommend inclusion and exclusion criteria for pancreas donors and 
pancreata that will be used for islet cell transplantation. Describe 
the clinical setting with suggested physiological and pharmaceutical 
interventions to maintain the donors until excision of the pancreas has 
been completed.

o Estimate the cost and identify the funding source(s) in place to 
obtain each pancreas.  Provide an estimate of the number of pancreata 
that must be harvested to fully transplant one recipient.    

Isolation

o Describe in detail the method planned to isolate islets from whole 
human pancreata. 

o Describe quality control (QC) and quality assurance (QA) provisions 
made at interim points in the procedure and for the final product.  

o Describe plans to optimize the isolation of islets for clinical and 
basic research.

o To comply with the intent of cGMP, isolation of islet cells should 
follow a set of current, scientifically sound methods, practices or 
principles that are implemented and documented during product 
development and production to ensure the consistent production of islet 
cells that can be administered safely and with consistent purity and 
functional capacity.  Describe elements of cGMP that would be used in 
the isolation of islet cells, such as: a) facility design to control 
operations; b) adequate documentation/records; c) production and 
process controls; d) quality control/assurance; e) validation; f) 
equipment and reagents that are calibrated/qualified; g) personnel that 
are trained and certified; h) traceability; and i) environmental 
monitoring.  It is expected that each ICR will be capable of FDA 
certification for cGMP, initially to support Phase I trials, and 
subsequently, Phase II clinical trials.

o Describe final product specifications for islet cell preparations, 
such as: a) presence of non-islet cells; b) absence of infectious 
agents; and c) sterility. Describe the specifications that will certify 
that islet cells are suitable for use by investigators at a recipient 
institution.

o Cite QC and QA assay measurements obtained from prior islet cell 
isolations. List the clinical measurements and end points used to 
determine islet cell functionality if they were transplanted into 
animals or humans.  Describe variations in isolation technique that are 
known to affect islet cell sterility, viability or function. 

o Describe measures to maintain sterility, viability, and function of 
islet cells that are distributed to investigators at both ICR and non-
ICR locations.

Distribution

o Propose how the Steering Committee should prioritize investigators’ 
requests for islet cells, for both clinical and basic research 
protocols, and how islet cells should be allocated between ICR and non-
ICR institutions, acknowledging that the Steering Committee will 
establish the procedures employed. 

o Describe research plans to determine if isolated islet cells can be 
shipped to sites outside of the ICR institution.

o Provide the research study plans through which the harvesting, 
maintenance and shipping of human islet cells will be optimized for 
future clinical protocols.

o The duration of time between harvest and transplantation is an 
important determinant of subsequent islet cell function.  Describe 
means by which this would be minimized within the ICR.

o Describe a) product containers; b) closures; c) labeling; d) 
sterility precautions; and e) packaging and handling procedures that 
will be employed enroute to the transplantation facility.

Transplantation

o Describe the location of the ICR relative to the location of the on-
site transplantation facility. 

o Cite prior local experience or collaborations with other 
investigators in the transplantation of islet cells. If the applicant 
has had no prior experience with islet transplantation, an investigator 
at the applicant's institution with experience in the field should be 
named, with a letter describing that experience, proposed contribution 
and intention to collaborate with the ICR on protocols involving islet 
cell transplantation. 

o Define the inclusion and exclusion criteria for type 1 diabetic 
candidates for islet cell transplantation.

o Describe pre-transplant medical testing and follow-up of diabetic 
patients that are eligible for islet cell transplantation.  Identify 
the funding source(s) to support these tests.

o Propose the process by which islet cells are prepared and infused 
into the recipient.  

o Describe the tests to assess the function of transplanted islet cells 
in vivo and define a data analysis plan to compare pre-transplant and 
post-transplant test results.  Identify the source of funds to support 
such follow up. 

o Describe the post-transplant monitoring plan.  How will a transplant 
be deemed successful?  What criteria will determine if an additional 
transplant is necessary?  

Protocol development

o Describe the approach for further protocol development, optimization 
and implementation of islet cell transplantation within the ICR 
network. 

o Identify all existing and planned sources of  peer-reviewed  funding 
that to be used in support of research studies relevant to this RFA.

Administrative and bioinformatics coordinating center (ABCC)

o Each application for the ABCC award must propose the procedures to 
administer the ICR Program, identify functions common to all ICRs that 
will be facilitated, describe the procedures that will maintain a 
current database and manage an intranet web site.  Only one ABCC will 
be selected based upon peer-review of these proposals.  

o Convey an understanding of the scientific, statistical, logistical, 
and technical issues underlying multi-center studies, including those 
relating to islet cell isolation and islet cell transplantation.

o Describe the qualifications of the applicant to take a leadership 
role in the area of study design, statistics, logistics, data 
acquisition and management, patient confidentiality, handling of 
laboratory specimens, quality control, data analysis, and network 
coordination. 

o Address the expertise, training and experience of the investigators 
and staff, including the administrative abilities of the principal 
investigator, co-investigators, and their time planned to devote to 
coordinate the ICRs.  This should specifically include relevant 
experience in operating a “coordinating center” of the kind described 
in this RFA.

o Provide a plan to acquire, transfer, manage, analyze and monitor 
basic laboratory information and clinical data generated through the 
use of ICR resources.

o Propose a process to coordinate the activities of all of the ICRs and 
those of Steering Committee.  Include the administrative, supervisory, 
and collaborative arrangements for achieving the goals of the program, 
and a willingness to cooperate with the ICRs and Funding Entities.

o Describe the facilities, equipment, and organizational structure 
currently available to coordinate ICR basic and clinical research 
activities.

o Describe how assay and disbursement data will be tracked for each lot 
of islet cells.

o Outline the procedure to collate and analyze data from ongoing 
clinical and basic research studies that have either been approved by 
the Steering Committee or use ICR resources.

o What data management services will be provided to the ICRs?

o Provide a description of the statistical support for protocol design 
and analyses of completed protocols.

o Describe the plan to interact with the DSMBs that are responsible for 
oversight of the clinical protocols that utilize ICR resources.

o Propose how timely reports will be made to DSMBs, the Steering 
Committee, the Funding Entities and other relevant oversight and 
regulatory bodies.

o Detail how privacy and security of all patient information as well as 
access by controlled authorization will be ensured.

o Describe how investigators would be assisted in the preparation of 
abstracts and manuscripts and how they would be tracked.

o Justify the proposed budget and personnel requested.

Since human somatic cell transplantation involves the administration of 
materials of biological products, it is regulated by the Center for 
Biologics Evaluation and Research (CBER), FDA.  IND applications are 
filed concerning clinical use of such products.  Respondents to this 
RFA should convey their familiarity with such requirements for 
clinical, pre-clinical and animal studies.

CBER has prepared documents relevant to this RFA that include:

o “Points to Consider in Human Somatic Cell Therapy” (1991)  

o “Points to Consider in the Production and Testing of New Drugs and 
Biologicals Produced by Recombinant DNA Technology” (1985) 

o “Points to Consider in the Characterization of Cell Lines Used to 
Produce Biologicals” (1987) 

o “Points to Consider in the Manufacture and Testing of Monoclonal 
Antibody Products for Human Use” (1987) 

o “Points to Consider in the Collection, Processing, and Testing of Ex-
Vivo Activated Mononuclear Leukocytes for Administration to Humans” 
(1989)

Copies of Points to Consider documents are available from:

The Division of Congressional and Public Affairs
CBER
HFM-12
1401 Rockville Pike, Suite 200 N
Rockville, MD  20852-1448
Telephone:  (301) 594-0830

CBER staff members are also available to respond to questions at (301) 
594-0830.

BUDGET AND RELATED ISSUES

Applicants should complete the budget information as directed in the 
PHS 398 application form.

Allowable costs

In order to fully achieve the goal of this initiative, up to six ICRs 
are proposed for support. The award will provide up to $300,000 per 
year in direct costs for each ICR.  An award of up to $700,000 direct 
costs will be awarded annually to the ABCC for support of 
administrative and bioinformatics activities.  

During the course of the project period, it is anticipated that 
technologies such as islet cell isolation and shipping, transplantation 
techniques, and immune suppression will improve and the proposed 
protocols may change.  Accordingly, it is expected that the 
investigators will adjust their scientific projects to accommodate such 
changes.  During the course of the award, the Steering Committee will 
meet at least semi-annually and workshops to review new developments in 
the field will be held periodically. 

Applications should present five budget periods of 12 months each that 
provide adequate budget justification for all applicable direct and F&A 
costs.  An estimate of personnel costs needs, including the principal 
investigators, other professional and support staff must be included.  
A minimum effort of 0.25 FTE is required for the ABCC Director and each 
ICR director and sub-project principal investigators.  Estimates of 
travel costs to Steering Committee and Data Committee meetings as well 
as a statement that indicates a willingness to participate in these 
meetings must also be included.  

Applicants submitting an ABCC application requesting $500,000 or more 
in direct costs for any year must obtain approval from NCRR program 
staff listed in INQUIRIES before submitting the application. The 
applicant must identify, in the cover letter that is sent with the 
application, the NCRR staff member who agreed to accept assignment of 
the application. 
Non-Allowable Costs:

The grant award for this RFA may not be used to pay for patient care 
costs.  Such costs include, but are not limited to: a) transportation 
and hospital care for organ donors; b) transportation, testing and 
monitoring of potential islet cell transplantation recipients; and d) 
inpatient or outpatient costs related to islet cell transplantation or 
other clinical studies using such preparations. 

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED 
UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW

The RFA label available in the PHS 398 (rev. 4/98) 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.  Line 1 should indicate 
whether the application is for an award as an ICR or ABCC.  In addition 
the RFA title and number must be typed on line 2 of the face page of 
the application form.  

Submit a signed, typewritten original of the application, including the 
Checklist, and two signed photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
Two Rockledge Centre, Room 1040-MSC7710
6701 Rockledge Drive
Bethesda, MD  20892-7710
(or Bethesda, MD  20817 if express mail or courier service is used)

At the time of submission, three additional copies of the application 
must be sent to the Deputy Director, Office of Review, NCRR, at the 
address listed under INQUIRIES.

Applications must be received by March 21, 2001.  If an application is 
received after this date it will be returned to the applicant without 
review.

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.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude 
the submission of substantial revisions of an application already 
reviewed, but such applications must include an introduction addressing 
the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the 
Center for Scientific Review and for responsiveness by NCRR in 
collaboration with NIDDK.  Applications that are incomplete or non-
responsive will be returned to the applicant without further 
consideration.  Applications must adhere to the page limitations and 
Special Application Requirements noted under the section APPLICATION 
PROCEDURES above to be considered responsive.  
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 Office of Review, NCRR in accordance with 
the review criteria stated below.  As part of the initial merit review, 
all applications will receive a written critique and may 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, assigned a priority score, and receive a 
second level review by the National Advisory Research Resources 
Council, and the NIDDK Advisory Council.

Review Criteria

The goals of NIH-supported research are to advance understanding of 
biological systems, improve the control of disease, and enhance the 
health of humankind.  The scientific and technical merits of the 
proposed activities and the organizational plans for participating in 
this cooperative agreement and the extent to which they address the 
overall goals and objectives of the RFA will be reviewed.  

Reviewers will be asked to provide written comments on the ICR 
applications for:

o Responsiveness and innovative approaches to  Major objectives of this 
RFA;

o Quality of the pre-clinical data and experience in translating them 
into clinical protocols;

o Plans to integrate institutional projects with shared cores and to 
make cores and resources available to other ICRs and NIH-supported 
investigators; 

o Prior experience in organizing and oversight of multi-centered basic 
and translational research studies and plans to extend this to the 
ICRs;

o Adequacy of laboratory and ancillary facilities and equipment;

o Evidence of institutional support;

o Experience in the field of human islet cell research and cellular 
transplantation research;

o Adequacy of the process design, methods, and analyses to be used;  

o Letters of planned or existing collaboration from clinical 
researchers who will perform pre- and post-transplantation studies 
using ICR-generated islet cells;  

The ABCC applicants will be evaluated on the basis of:

o Responsiveness and innovative approaches to the major objectives of 
this RFA;

o Experience in the coordination and oversight of relevant, multi-
center trials;
o Planned organization, oversight and administration of the ICR 
Program;

o Qualifications of personnel;

o Availability of computer technologies and equipment suitable for ICR 
oversight;

o Letters of reference from principal investigators who have 
participated in multi-center basic research or clinical research trial 
overseen by the ABCC applicant. 

Both the ICR and ABCC applications will also be evaluated with regard 
to the likelihood that they will function in a synergistic manner and 
interact well with the other proposed components .  Appropriateness of 
their proposed budgets will also be considered.

In addition to the above criteria, in accordance with NIH policy, all 
applications will be reviewed with respect to the following:

o The adequacy of plans to include, recruit and retain both genders, 
minorities and their subgroups, and children as appropriate for the 
scientific goals of the research.

o The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the 
project proposed in the application.  

o The training course(s) taken by key personnel addressing the 
protection of human subjects must be included in the application.  For 
this purpose, key personnel are defined as individuals who design or 
conduct clinical research protocols.  

o A discussion of data safety monitoring must also accompany the 
application.

Schedule

Letter of Intent Receipt Date:  February 8, 2001
Application Receipt Date:       March 21, 2001
Peer Review Date:               May-June, 2001
Council Review:                 September 13-14, 2001
Anticipated Award Date:         September 2001

AWARD CRITERIA

Factors that will be considered in making awards include: a) the 
scientific merit of the proposed program as determined by peer review, 
the multi-disciplinary nature of the proposed studies, and the quality 
of the response to the requirements stated in this RFA; b) relevance to 
the overall programmatic balance and priorities of NCRR and NIDDK and 
sufficient compatibility of features proposed in the research plan and 
qualifications of the investigators to make a collaborative program 
within the ICRs a reasonable likelihood; and c) the availability of 
funds.  The earliest anticipated date of award is September 2001.  Some 
consideration will also be given to geographic diversity.  The award 
will be subject to administrative review by NCRR and NIDDK staff upon 
receipt of each annual non-competitive renewal application.

INQUIRIES

Inquiries concerning this RFA are encouraged.  We welcome the 
opportunity to clarify any issues or respond to questions from 
potential applicants.

Direct inquiries regarding programmatic issues to:

Richard Knazek, M.D. 
Medical Officer
Clinical Research Area
National Center for Research Resources
One Rockledge Centre, Room 6030
6705 Rockledge Drive, MSC 7965
Bethesda, MD  20892-7965
Telephone: (301) 435-0792
FAX: (301) 480-3661
Email: richardk@ncrr.nih.gov

Direct inquiries regarding review issues to:

John Meyer, Ph.D.
Deputy Director, Office of Review
National Center for Research Resources
One Rockledge Centre, Room 6018
6705 Rockledge Drive, MSC 7965
Bethesda, MD 20892-7965
Telephone: (301) 435-0806
FAX: (301) 480-3660
Email:  meyerj@ncrr.nih.gov 

Direct inquiries regarding fiscal matters to:

Ms. Mary Niemiec
Section Grants Management Officer
Office of Grants Management
National Center for Research Resources
One Rockledge Centre, Room 6086
6705 Rockledge Drive, MSC 7965
Bethesda, MD  20892-7965
Telephone: (301) 435-0844
FAX:  (301) 480-3777
Email:  maryn@ncrr.nih.gov 

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.  Reviewers are cautioned 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 all priority areas.  Potential applicants may obtain a copy 
of "Healthy People 2010" at http://www.health.gov/healthypeople/.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are 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 research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm : 
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age 
of 21) must be included in all human subjects research, conducted or 
supported by NIH, unless there are clear and compelling 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 was published 
in the NIH Guide for Grants and Contracts, March 6, 1998 and is 
available at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 

Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES.  Program staff may also provide 
additional relevant information concerning the policy.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.333.  Awards are made under authorization of the Public Health 
Service Act, Titles III and IV, Sections 301, 479, and 480, as amended, 
Public Laws 78-410 and 99-158, 42 U.S.C. 241, 287, and 287a, as 
amended, and administered under NIH grants policies and Federal 
Regulations 42 CFR 52 and 45 CRF Part 74 and 92.  This program is not 
subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and promote the non-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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