###### **Biological Response Modifiers AdvisoryCommittee** 

###### **Meeting #36** 

###### **Allogeneic Pancreatic Islets for Type 1 Diabetes** 

###### **October 9-10, 2003** 

######### Manufacturing & Product Quality Questions

1.  A key component for ensuring control of a validated islet
    manufacturing process is the use of pre-defined acceptance criteria
    to ensure that suitable donor organs with maximal potential for
    yielding adequate numbers of islets are utilized for manufacturing
    allogeneic islets, while unsuitable organs are excluded. Acceptance
    criteria may include donor suitability determination, organ
    characteristics, harvesting conditions, and transport conditions.
    Most, if not all, of this information is currently collected by
    sponsors of islet INDs. Please discuss the use of this manufacturing
    experience data as a basis for developing pre-defined acceptance
    criteria for source organs.

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2.  Based on a given donor organ's characteristics, investigators
    frequently "customize" an islet isolation procedure by using
    different reagents, reagent concentrations and processing methods
    such that no two islet isolation procedures are exactly alike.
    However, cGMPs and BLA requirements necessitate the use of a
    well-defined, well-controlled manufacturing process. Is it
    reasonable to expect that criteria or algorithms can be developed,
    based on data collected during IND studies, to predetermine under
    what conditions the use of a specific reagent, reagent
    concentration, or processing method is appropriate?

3.  Please discuss any assay or assays that are currently, or could be,
    performed on the final islet product before patient administration,
    which may be predictive of the ability of the islets to perform as
    expected after patient administration.

4.  What should be key criteria for demonstrating allogeneic islet
    product comparability? Please discuss appropriate analytical assays,
    bioassays, preclinical studies, and clinical studies that may be
    required.

######### Clinical Data Questions

1.  Please discuss the clinical importance and limitations of each of
    the outcomes listed below. Please discuss each outcome with respect
    to its use in providing substantial evidence of efficacy if adequate
    and well-controlled clinical studies demonstrate a robust and
    durable treatment effect on the outcome.

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a.  "Insulin independence." This outcome may be defined in many ways
    but, in addition to any other definitions you regard as important,
    please specifically comment upon the following definition:
    "cessation of insulin treatment or decrease in insulin requirement
    in the setting of sufficient glycemic control." If you regard this
    as an important endpoint, please comment upon what you regard as
    evidence of "sufficient glycemic control."

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c.  Use of hemoglobin A1C, serum C-peptide concentration and mean
    amplitude of glycemic excursions (independently or in various
    composites) as measures of glycemic control and/or islet function.

d.  Acute diabetic complications. Please identify those complications
    that you regard as important outcomes (e.g., episodes of
    hypoglycemic unawareness, hospitalizations, death).

e.  Long-term diabetic sequelae. Please identify those complications
    that you regard as important outcomes (e.g., nephropathy,
    neuropathy, etc.).

f.  Other outcomes you regard as important.

######### Clinical Data Questions (continued)

2.  Regarding the overall clinical development program for a sponsor's
    allogeneic islets, please discuss the importance and/or
    meaningfulness of the following types of clinical data with respect
    to the ability to form a risk-benefit assessment for the product.

    a.  Certain types of safety data: Specifically, the nature and
        extent of "long-term" clinical data that must be submitted in
        order to form a reasonable risk-benefit assessment. For example,
        must clinical follow-up for a certain number of subjects extend
        over a protracted period of time (e.g., 3, 5 or more years)? If
        so, please comment upon what you regard as a reasonable period
        of time and describe the types of data that must be obtained
        during this period, both pre- and post-licensure.

    b.  Historically controlled clinical data: Specifically, the
        appropriateness of the use of historical controls in the
        development program for a product, and whether data from studies
        that use no concurrent controls could be sufficient to provide
        substantial evidence of effectiveness of the product.

    c.  Clinical data from studies that only enrolled subjects with
        certain specific baseline characteristics: Specifically, the use
        and potential generalizability of clinical data from studies
        that enrolled a small subset of subjects with type 1 DM (for
        example, only subjects with a history of certain manifestations
        of "hypoglycemic unawareness"). Additionally, please discuss
        those baseline characteristics that you regard as important for
        a sponsor to consider in the clinical development of their
        product (e.g., age, extent and nature of diabetic complications,
        etc.).