Questions for the committee: preclinical and clinical issues in
allogeneic islet therapy

# **1. Immunosuppression**

Immunosuppression is important for survival of allogeneic islets, but
the immunosuppressive therapy is associated with risks to the patients,
such as infection, renal injury, possible malignancy and possible islet
injury. Most of the published reports of allogeneic islet therapy and
most clinical investigations are in patients on existing
immunosuppression because of prior organ (usually kidney)
transplantation. However, the immunosuppressive regimen used in kidney
transplantation may not be optimal for islet products, and it may be
difficult to standardize the immunosuppression regimens when patients
enter the islet cell study.

-   Are current data from preclinical models of islet only therapy
    and/or clinical studies of kidney/islet transplantation sufficient
    to support islet only therapy?

-   If no, please discuss the kinds of animal and human data needed to
    justify the added toxicity of immunosuppression in islet-only
    therapy.

-   What is/are the most appropriate immunosuppressive regimen(s) to use
    for islet - only studies? What additional animal studies should be
    done to explore/optimize the regimen(s)?

-   Which patients (demographics and disease-related aspects) are most
    appropriate to include in studies of islet -only therapy?

**2. *Donor-recipient matching***

Historical data in the ITR on HLA mismatch, sex compatibility and ABO
identity for 123 single donor islet recipients from 1990-1997 reveal no
clear pattern with regard to survival of islet allografts.

-   Are other pre-clinical or clinical data available which address the
    immunogenicity of islet preparations?

-   If no, then, given the absence of clear data on the immunogenicity
    of islet preparations, please comment on the minimum criteria
    (degree of HLA disparity etc.) to be used for donor-recipient
    matching.

-   Does the committee agree that data on donor-recipient matching
    should continue to be collected?

**3.** ***Organ quality***

-   Which factors related to quality of the donor organ (e.g., cold
    ischemia, warm ischemia, islet preparation methods), can best be
    assessed in preclinical studies?

-   What endpoints in pre-clinical models would be useful in decisions
    regarding improved islet product quality?

**4. *Route/site of islet cell product administration***

Most allogeneic islet preparations are administered via the portal vein,
although other routes have occasionally been used; e.g., subcutaneous
implants, peritoneal implants. The latter are more common with
encapsulated devices and have the advantage of being accessible to
surgical removal.

-   Is it desirable for islet preparations to be in direct contact with
    the portal circulation?

-   Please discuss the safety considerations of intraportal injection of
    islets. Are there procedural steps that may facilitate safe
    injection of the islets, such as portal pressure monitoring,
    portography or other procedures? Please discuss methods to identify
    those patients at high risk for complications related to intraportal
    injections of islets.

-   Please discuss options for other routes of administration and the
    implications with respect to immunogenicity (e.g., advantages of
    "immunoprivileged" sites).

-   Please discuss the utility of the various animal models to evaluate
    route/site of administration of islet preparations.

5.  ***Glucose control***

High levels of glucose during the peri-implant period may injure islets.
Some protocols require "tight" control during this period.

-   What should the level of glucose control be during this period? How
    long should this level be maintained? What types/schedules of
    insulin would be best to achieve this level control?

-   Can/should pre-clinical studies be performed to assess the impact of
    tight glucose control during the peri-implant period?

6.  ***Islet dose***

-   How should the "dose" of islets be defined; e.g., based on islet
    equivalent number, volume, or secretory function?

-   Should varying doses of islet preparations be evaluated in animal
    models, and if so, how is this best done?

-   How might the evaluation of dose in animal models improve our
    approach to dosing in clinical investigations

-   Should clinical studies designed to explore different islet dosages
    be conducted?

7.  ***Second and subsequent islet therapy***

-   Provided an organ is available, what criteria, e.g., biochemical
    evidence of graft failure, length of function of first graft, etc.)
    are appropriate for a second islet transplant?

-   Are data available to indicate whether sensitization is likely to
    occur with graft rejection, decreasing the success of subsequent
    engraftment?

-   How should second and subsequent islet product transplants be
    evaluated in animal models?

8.  ***Outcome measures***

a\. Activity measures in early clinical studies include C-peptide,
hemoglobin A~1c~, glucose tolerance, insulin usage, hypoglycemic
episodes, and patient diaries.

-   Please comment on the appropriateness of these values. Should other
    measures such as somatostatin and glucagon also be evaluated?

-   Should these and other potential endpoints be assessed in animal
    models, and if so, which ones?

-   What criteria should be used to determine loss of graft function and
    the appropriate time to withdraw immunosuppression?

b\. Efficacy endpoints in phase 3 trials should be clinically relevant
measures, or surrogates that reflect clinical benefit. In cases of
serious or life threatening conditions where the new product represents
an advance over existing therapies, the agency may grant "accelerated
approval" based on studies showing an effect on a surrogate endpoint
that is reasonably likely to predict clinical benefit. In such cases,
studies are required post licensure to confirm the clinical benefit.

-   Please discuss potential efficacy endpoints for phase 3 trials of
    allogeneic islet products.

-   Could improved glucose control, as measured by glycosolated
    hemoglobin, if durable, be an acceptable endpoint for accelerated
    approval? If so, how durable does the effect need to be and in what
    population (e.g., "brittle diabetics") would the effect most easily
    be demonstrated? What types of studies would be optimal for
    confirming clinical benefit?