The Clinical Research Division of the National Center for Research
Resources (NCRR), the National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK), and the Juvenile Diabetes Research Foundation International
(JDRFI) held a grantsmanship workshop to assist potential applicants for the "Human
Pancreatic Islet Cell Resource," previously published as Request for Applications
(RFA) RR-01-002 in the NIH Guide for Grants and Contracts (http://grants.nih.gov/grants/guide/rfa-files/RFA-RR-01-002.html.)
This technical workshop allowed applicants and NIH staff to discuss and clarify
any issues or questions related to the application process. Additional information
is located at http://grants.nih.gov/grants/guide/notice-files/NOT-RR-01-004.html
Welcome and Introductory Remarks, Dr. Richard Knazek, NCRR/NIH:
Dr. Knazek welcomed the participants and explained that representatives of the
NCRR, NIDDK, JDRFI, National Institute of Allergy and Infectious Diseases (NIAID),
and Food and Drug Administration (FDA) would discuss how their programs would
complement or guide the Islet Cell Resource Centers.
The overall purpose of this workshop was to reiterate the goals and mechanisms
outlined in the RFA referenced above and respond to participants' questions.
Presentation by Dr. Louise Ramm, NCRR/NIH:
Dr. Ramm, NCRR Deputy Director, outlined some of the programs available through
NCRR to facilitate the research of the participants:
- Biotechnology - National and regional centers that develop and provide access
to advanced biomedical research technologies such as NMRs, MRIs, mass spectrometry,
and synchrotrons, as well as to cutting-edge shared instrumentation.
- Comparative Medicine - availability of various resources, such as mutant mouse
repositories, the Regional Primate Research Centers, and many invertebrate repositories.
- Research Infrastructure - the IDeA program to foster research in states with
historically low success in obtaining NIH grants, and construction and facilities
improvement grants to improve and expand research facilities.
- Clinical Research - the General Clinical Research Centers, the National Gene
Vector Laboratories, the National Disease Research Interchange and the K23, K24
and K30 training grants.
Detailed descriptions of these programs are available through the NCRR Web site at http://www.ncrr.nih.gov.
Presentation by Dr. Joan Harmon, NIDDK/NIH:
Dr. Harmon described the Balanced Budget Act of 1997 and the impact that its $27M
annual provision to NIH programs has had on developing programs to support research
on Type 1 Diabetes Mellitus. In addition, the NIDDK has continued support in this
area:
- Six sites in the United States are funded to conduct human islet transplants into humans. Additionally, there is a site in Canada and one in Germany.
- Four Trans-NIH RFAs were published in 1998 and three in 1999.
- Six grants funded by the NIDDK, the NIAID, and the JDRFI were awarded in 1999 to support the transplantation of human pancreatic islets into patients.
- $3.5 M was awarded in 2000 to develop new strategies for treatment of Type 1 Diabetes. Two grants support human islet transplants into humans.
- Currently, there are six open RFAs or RFPs that are relevant to islet cell transplantation:
- Beta cell biology consortium ($7.25M)
- Cooperative Multicenter Research Network to Test Glucose Sensors in Children with Type 1 Diabetes Mellitus ($2M)
- Mouse Models of Diabetic Complications ($4.5M)
- Gene Therapy Approaches for Diabetes and Its Complications ($1M)
- Beta Cell Transplant Registry ($0.6M)
- Islet Cell Resource Centers ($3M).
In December 2000, the U.S. Congress appropriated
an additional $70M per year for the next three years to increase the support for
Type 1 Diabetes research. NIDDK has the responsibility to allocate these monies
on behalf of the NIH. A portion of these funds ($3 M) will be made available to
pay for the acquisition of pancreata by the Islet Cell Resource Centers over the
next two years.
Click Here for the presentation.
Presentation by Dr. Daniel Jang, JDRFI:
Six institutions have been funded by the JDRFI to isolate and distribute human
pancreatic islets for use in basic research. Three of these centers distributed
approximately 8x106 islets to 43 investigators last year. Recently, these isolation/distribution
centers were charged with the responsibility of providing half of their islets
for use in human clinical transplantation protocols. While some islets have now
been transplanted, information on the outcome of those procedures is not yet available.
Investigators should submit requests for islets directly to the JDRFI. Once approved,
investigators can approach the centers with their requests.
Click Here for the presentation.
Presentation by Dr. Daniel Rotrosen, NIAID/NIH:
Although NIAID is not a co-sponsor of the present RFA, its investigators will
be a user, via the Immune Tolerance Network (ITN), of islets generated by the
Islet Cell Resource Centers. Dr. Rotrosen described how the ITN program has been
designed to duplicate and verify the very encouraging results of the Edmonton
islet transplantation program. Forty patients will be transplanted at seven U.S.
sites, one in Canada and three in Europe. In the future, there will likely be
changes in the preparation and isolation procedures, with possible in vitro expansion,
single transplantations, less immunosuppressive regimens and stem cell-derived
islets. Discussions are taking place with HRSA and HCFA to review costs and prioritization
of transplantable pancreata for islet isolation protocols.
Use of the Edmonton protocol IND will be made available to qualified investigators
through the ITN.
At an appropriate time, specifications of Liberase lots used by the ITN sites
will be made available to facilitate the testing and selection of Liberase lots
for use in other studies.
Click Here for the presentation.
Presentation by Dr. Darin Weber, CBER/FDA:
The Division of Cellular and Gene Therapies within the FDA Center for Biologics
Evaluation and Research (CBER) has oversight responsibility for transplantation
of allogeneic pancreatic islet cells. Regulations concern pancreas procurement,
control and consistency of islet production, subsequent safety testing and characterization
of islets, and adherence to current Good Manufacturing Practices (cGMP). Product
characterizations include identity, purity, potency, stability, and other specifications.
Islets must be generated using procedures guided by cGMP regulations. cGMP is
defined as the set of current, scientifically sound methods, practices or principles
that are implemented and documented during product development and production
to ensure consistent manufacture of safe, pure, and potent products.
Elements of cGMP are facility design, adequate documentation and records, production
and process controls, QC/QA, validation, equipment qualification, training and
certification of personnel, and environmental monitoring. cGMP are minimal standards
that increase in stringency as a protocol progresses from Phase I toward Phase
IV.
Omissions in islet transplantation INDs submitted to CBER are not uncommon. Frequently,
data to support the consistency of manufacturing are lacking, shipping procedures
have not been validated, and no qualification program exists for critical reagents.
The CBER contact for islet preparation issues is Dr. Darin Weber (weberd@cber.fda.gov,
301-827-5102). Facility design issues may be discussed with any individual in
the Division of Manufacturing Product Quality at 301-827-3031. Mr. Robert Sausville
is the current contact person. General CBER information is available at http://www.fda.gov/cber/guidelines.htm.
IND submission packets may be obtained at http://www.fda.gov/cber/ind/ind.htm
while links to guidance documents relevant to this RFA are located at http://grants.nih.gov/grants/guide/notice-files/NOT-RR-01-004.html.
Click Here for the Presentation 1.
Click Here for the Presentation 2.
Presentation by Dr. Richard Knazek, NCRR/NIH:
The present RFA, co-sponsored by NCRR, NIDDK and JDRFI, is divided into two parts-the
Islet Cell Resource Centers (ICRs) that will provide islets and an Administrative
and Bioinformatics Coordinating Center (ABCC).
The purpose of the ICRs is to develop and employ techniques to isolate, purify,
characterize, and distribute human pancreatic islets for transplantation into
diabetic patients.
An ICR must be an identifiable unit either within a single institution or within
a group of collaborating institutions. It will likely be composed of individuals
from various departments, each of whom possesses skills that are unique to that
discipline. The ICR must be able to coordinate and facilitate relevant activities
between laboratory investigators and clinical researchers.
An ICR will be responsible for procuring whole pancreata while acquiring relevant
data about the donor and information on the procedures employed during the harvest.
In the course of isolating each batch of islets, the ICR will perform research
intended to improve and optimize the isolation techniques and yields, their viability
and function, storage and handling procedures. It will characterize the islets
obtained, perform appropriate QA/QC procedures, and distribute the islets to qualified
investigators both within and outside of the ICR. All such investigator requests
will have to be reviewed and approved by the ICR Steering Committee since investigators
may request islets for laboratory research, as previously described, as well as
clinical transplantation protocols.
Follow-up information on transplant recipients will be obtained by the ICRs to
develop algorithms that enable laboratory and patient data to predict the clinical
effectiveness of a specific batch of islets.
Each ICR must agree to participate as members of the ICR Steering Committee and
abide by the Policy and Procedure Document that they will help to construct.
ICR applicants should have demonstrated significant research expertise and experience
in islet cell transplantation and documented their ability to generate adequate
numbers of qualified, functional islets for human transplantation. The cell processing
facility should be established at the time of submission of the application. The
facility should meet the production needs of this RFA and satisfy the relevant
FDA requirements.
To be eligible for consideration, an ICR applicant must be a domestic, not-for-profit
organization that can be either public or private or an eligible government unit.
Each ICR application should address, at a minimum, several items: 1) qualifications
of personnel proposed to be involved both in and with the ICR; 2) pre-clinical
data generated by members of the proposed ICR unit; 3) the existing laboratories,
assays and islet preparation facilities; 4) any unique facilities or assays that
could serve as core resources for the ICR network; 5) clinical studies in which
the proposed personnel have participated; 6) how the ICR would interact with the
Steering Committee and ABCC; 7) any relevant human subjects issues; and 8) a data
and safety monitoring plan.
The ICRs will not develop an independent Data and Safety Monitoring Board (DSMB).
Nonetheless, the applicant should present a plan to maintain the safety and privacy
of the transplant candidates in associated clinical protocols. The operation of
DSMBs is the responsibility of the parent institution, funding organization, or
sponsor of those clinical protocols.
The intent of this RFA is to develop the ICRs as regional resources. To accomplish
this, cooperation and synergy will be critical components within the ICR network.
Accordingly, an ICR applicant should propose plans to: 1) structure the ICR unit
in a manner that allows participation with and facilitation of the function of
other ICRs; 2) share unique technologies and data within the ICR networks; 3)
collaborate with investigators involved in relevant laboratory and clinical research-it
is strongly advised that clinical contacts be established to permit transplantation
of ICR-generated islets; 4) participate in the Steering Committee evaluation of
requests for ICR islets; and 5) cooperate with other ICRs to transform this experimental
procedure into a practical clinical therapy.
An ICR application should address 1) donor issues; 2) compilation of harvesting
data; 3) the ability to obtain critical reagents and biological materials-alternative
sources of such materials may be necessary as exemplified by the current unavailability
of clinical grade Liberase; 4) the appropriateness of the proposed QA/QC process;
5) compliance with FDA guidelines; 6) plans to identify cellular characteristics,
physiological responses and genomic qualities that correlate with longevity, function,
portability and clinical usefulness of islets; 7) distribution of ICR resources
on equitable and scientifically sound bases; and 8) plans to facilitate laboratory
and clinical research protocols, both within and outside of the ICR.
Upon receiving a favorable review and fundable priority score, the proposed ICR
must undergo a site inspection to document compliance with relevant FDA guidelines.
Such an inspection would be performed by a qualified commercial organization with
the associated costs being defrayed by NCRR. A favorable inspection report will
be required as a condition of award.
The ABCC requires a separate application that is independent of any ICR. Such
applications will undergo peer review, overseen by the Office of Review within
NCRR, separate from ICR application reviews. If a single institution applies for
designation as both an ICR and ABCC, two separate applications must be submitted.
Each should describe how the two units will maintain their independence and avoid
conflicts of interest.
Applicants seeking designation as the ABCC must be a domestic organization and
may be either not-for-profit or for-profit, public or private entities.
One ABCC will be selected to perform administrative functions for the ICRs and
Steering Committee by coordinating ICR activities, organizing meetings, and coordinating
the sharing of unique assays and core facilities between ICRs. It will also house
the bioinformatics core, maintain the consolidated database, and compile and analyze
data.
The ABCC application should describe, at a minimum 1) its experience in coordinating
multi-center research programs; 2) the experience of its key personnel; 3) its
biostatistical and bioinformatics experience and plans; 4) available resources;
5) its proposed function and how it would facilitate the effectiveness of the
Steering Committee, each ICR and the ICR network; 6) plans to coordinate ICR cores;
7) human subjects issues and 8) a data and safety monitoring plan.
The anticipated award date is September 2001 with its duration being five years.
The award mechanism is the Cooperative Agreement (U42). This is an assistance
mechanism in which there is substantial NIH scientific and programmatic involvement
with the awardees. However, NIH does not assume direction of activities. Rather,
each ICR Director will retain primary responsibility for the performance of that
ICR while the ABCC Director retains primary responsibility for the performance
of the ABCC.
The Steering Committee will provide scientific and administrative guidance to
both the ABCC and the ICRs within the network. It will develop and promote collaborations
between ICRs and review and prioritize islet and resource requests submitted by
investigators both within and outside of the ICR network.
The Steering Committee will establish the Policy and Operating Procedures by which
it and the ICRs will function. It will develop guidelines for investigators' requests
and the requirements for laboratory and clinical research protocols that use ICR-generated
islets. The objectives, implementation and interactions of the ICR network will
be defined by the Steering Committee within this document. An example of such
a document is located at the Web site of the National Gene Vector Laboratory Coordinating
Center at http://www.iupui.edu/~iucc/ngvl. The Policy and Procedures document
must receive a favorable review by the Directors of NCRR, NIDDK and JDRFI before
it can be implemented.
The Steering committee will be comprised of ICR Directors, representatives of
the NCRR, NIDDK and JDRFI and ad hoc experts. NCRR, NIDDK, and JDRFI will select
the Chairperson.
Requests for islets or resources will be submitted to the ABCC. The ABCC Director
will distribute these requests to the Steering Committee members for review and
discussion at their next meeting. Upon favorable review, an ICR will be selected
to distribute islets to the requester. Data generated by both the ICR and investigator
will be entered into the ICR database by the ABCC. The ABCC will assist in data
analyses and share those results with the investigator and Steering Committee.
ICR awardees will have primary rights to their data developed under this award,
subject to the Government's right of access consistent with current Federal policies.
Click Here for the presentation.
Presentation by Jenelle Wiggins, NCRR/NIH:
It is anticipated that the infrastructure of as many as six ICRs will be supported
by up to $300,000 direct costs per year, per ICR. A proposed budget should accompany
each application based on this ceiling. Costs of obtaining pancreata will be defrayed
by the above-cited congressionally appropriated funds on an ad hoc basis. While
it is anticipated that such support for pancreas acquisition will total ~$3M for
FY '01 and '02, the proposed budgets should reflect neither those acquisitions
nor the costs of patient care nor the costs of immune suppression drugs. ICR applicants
should, however, indicate the number of pancreata that they plan to acquire annually.
The ABCC will be funded by up to $700,000 direct costs/year. A detailed budget
is required with each ABCC application.
Presentation by Dr. Charles Hollingsworth, NCRR/NIH:
The RFA application receipt date is March 21, 2001. Peer review will occur in
May or June 2001 to permit the National Research Resources Advisory Council to
consider these applications at its September 2001 meeting.
Conclusion
This summary is intended to outline points discussed at the workshop. Items addressed
within the RFA but not presented in this summary must still be considered when
responding to the RFA.
Although the RFA specified no page limit, applicants are encouraged to avoid submissions
that are unnecessarily voluminous.
Please direct programmatic inquiries to:
Richard Knazek, M.D.
Medical Officer
National Center for Research Resources
Division for Clinical Research Resources
One Democracy Plaza, Room 906
6701 Democracy Boulevard, MSC 4874
Bethesda, Maryland 20892-4874
Telephone: 301-435-0792
FAX: 301-480-3661
e-mail: KnazekR@mail.nih.gov
or
Joan T. Harmon, Ph.D.
Supervisor, Health Science Administration
National Institute of Diabetes and Digestive and Kidney Diseases
Two Democracy Plaza, Room 601, MSC 5460
Bethesda, MD 20892
Phone: 301-594-8813
FAX: 301-480-3503
Email: harmonj@ep.niddk.nih.gov
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