Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products

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Additional copies of this guidance are available from the Office of Communication, Outreach and Development (OCOD) (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm.

For questions on the content of this guidance, contact OCOD at the phone numbers listed above.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
September 2009

Contains Nonbinding Recommendations

INTRODUCTION

  • MANUFACTURING QUALITY AND CONTROL CONSIDERATIONS
    1. Demonstrating Quality Source Material
    2. Control of the Manufacturing Process
    3. Potency Testing
  • PRECLINICAL CONSIDERATIONS
    1. Goals of Preclinical Safety Studies
    2. Animal Models Appropriate for Use in Preclinical Studies
    3. Immunosuppressive Regimen
    4. Route of Administration
    5. Modified Allogeneic Islet Cell Products
    6. Potential for Reproductive, Developmental and Carcinogenic Risks
  • CLINICAL STUDY PROTOCOLS
    1. Design
    2. Eligibility Criteria
      1. Inclusion Criteria Considerations
      2. Exclusion Criteria Considerations
    3. Study Conduct
      1. Dosing
      2. Immunosuppressive Regimens
      3. Adverse Experience (Risk) Reporting
      4. Stopping Rules
    4. Study Endpoints
      1. Primary Endpoint
      2. Analysis of Other Key Clinical Outcomes
      3. Secondary Endpoints
        1. C-peptide
        2. Insulin requirements
        3. Health-related quality of life
    5. Data Analysis Plan
    6. Follow-Up

    • Contains Nonbinding Recommendations
    Guidance for Industry Considerations for Allogeneic Pancreatic Islet Cell Products

     

    This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

    1

    The following recommendations are provided to help you navigate some of the challenges unique to manufacturing islets that you may encounter in collecting chemistry, manufacturing, and controls data to support approval of your BLA.

    A. Demonstrating Quality Source Material

    Health Resources and Services Administration (HRSA) regulates organ procurement and allocation (see 42 CFR Part 121). However, consistency of islet cell product manufacturing is highly dependent on the quality of the organ delivered to the manufacturing facility. Therefore, you should consider having discussions with your local organ procurement organization, regarding collection of data for things such as:

    • Organ harvesting procedures;
    • Ischemia time (both warm and cold);
    • Organ preservation methods; and
    • Shipping containers and conditions.

    These data will be most useful in manufacturing if they are collected in a way that will allow you to correlate each parameter with manufacturing consistency and clinical outcome. These data should help you and your organ procurement organization to standardize procedures and establish predefined acceptance criteria2 for harvesting, packaging, and shipping the organ.

    Regardless of the degree of standardization of organ procurement, acceptance criteria for organ quality should be established to ensure that unsuitable pancreatic tissues are excluded from manufacturing. At a minimum, the donor testing and screening must meet the requirements for donor eligibility described in 21 CFR Part 1271, Subpart C – Donor Eligibility (see final rule, “Eligibility Determination for Donors of Human Cells, Tissues and Cellular and Tissue-Based Products”).3 In addition, FDA has published a “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps).”4 We recommend that you review this guidance to ensure that the donor qualification criteria described in your IND are consistent with current recommendations. Additionally, you should collect data and consider establishing acceptance criteria for other characteristics that may affect the quality of the final allogeneic islet cell product such as:

    • Organ size;
    • Extent of organ fibrosis;
    • Donor health status (especially any diabetic conditions);
    • Donor age; and
    • Donor body mass index.

    B. Control of the Manufacturing Process

    Manufacturing process variations may allow for increased yield and quality of islet cells. During investigational studies you should define the critical manufacturing steps that impact safety, purity, and potency and establish controls at these critical manufacturing steps. Examples of manufacturing controls that may improve allogeneic islet cell quality include:

    • Varying quantity (weight or units) of dissociation enzymes;
    • Varying digestion conditions such as time, temperature, and shaking;
    • Using certain additives (DNase, Pefabloc, etc.); and
    • Using short-term culture of varying length and condition.

    For the manufacturing controls referenced above, you should develop and establish specifications that are appropriate for your manufacturing process. Data collected during investigational studies may be important to support both your established specifications and the established limits of process variation. This should allow some flexibility in the exact procedures used for a specific pancreas, but should also ensure that the process is standardized for consistency.
    As part of establishing a processing algorithm, you should collect data to demonstrate how processing parameters affect the product potency. We also recommend that you determine, to the extent possible, the effect of processing parameter changes on clinical outcome.

    C. Potency Testing

    For a BLA, you must use an appropriate assay to measure potency of your allogeneic islet product that meets the regulatory requirements under 21 CFR 610.10. In general, assays for product potency are intended to show the ability of the product to effect a given result (see 21 CFR 600.3(s)).
    The accuracy, sensitivity, specificity, and reproducibility of the potency assay must demonstrate lot-to-lot consistency and stability of the product (21 CFR 211.165(a), (d), and (e); see section 351(a)(2)(C) of the Public Health Service Act (42 U.S.C. 262(a)(2)(C)). Many of the currently utilized biological assays measuring islet function are not rapid enough for use in routine lot-release testing. Therefore, we recommend that, during the IND process, you explore the development of rapid analytical assays for potency. For example, you could correlate the biological activity of the final product measured by restoration of euglycemia in a diabetic nude mouse with a rapid analytical assay. This correlation would help to ensure that your analytical assay is a reliable measure of potency, which could then be used for lot-release and should aid in product development.5

    6 if you are proposing innovative delivery methods for allogeneic islet cell products, you should demonstrate an adequate safety profile (e.g., safety of the delivery system and interaction of cells with the components of the delivery system) in animals prior to proceeding to clinical trials.

    E. Modified Allogeneic Islet Cell Products

    Although recommendations regarding the manufacturing, preclinical, and clinical studies for modified allogeneic islet cell products are beyond the scope of this guidance, a manufacturing change that results in a significant modification of the product characteristics should lead to the consideration of the need for additional preclinical studies. Encapsulation of allogeneic islets provides a useful example of a modification for which additional preclinical studies may be needed. For example, you should consider the need to provide data that support the safety of both the encapsulation material, including the safety of any likely synthetic or degradation products, and the final encapsulated islet product. You should also consider “proof of concept” studies to demonstrate that the encapsulated islets are able to function in an animal model of disease for a sufficient duration to suggest that the risk of clinical administration of the product is likely to be outweighed by the potential clinical benefit. Although data on immunological effects of encapsulated islets should be collected to the degree possible from the safety and “proof of concept” studies, additional focused preclinical studies and/or clinical monitoring of immunological effects of the encapsulation (both on activity of the islets and potential autoimmune pathologies) should be considered for encapsulated islet products.

    F. Potential for Reproductive, Developmental and Carcinogenic Risks

    At this time, sponsors of clinical trials for the administration of allogeneic islet cell products which are collected, isolated, and/or processed by conventional methods that are frequently reported in the scientific literature, are not expected to submit preclinical studies to address directly reproductive, developmental toxicity, and carcinogenic potential of these allogeneic islet cell products (e.g., literature). However, the potential need for reproductive, developmental, and carcinogenicity studies should be discussed with us in the context of each individual IND submission as some or all of these studies may be appropriate for those innovative products that incorporate novel features such as encapsulation or non-traditional cell source.

    7 

  • Secondary Endpoints
    1. C-peptide
      Plasma C-peptide levels have proven essential in monitoring islet graft viability and function during clinical trials and C-peptide levels should be measured during pivotal trials. C-peptide levels should not in themselves be used as primary clinical efficacy endpoints, but may be used as secondary endpoints.
    2. Insulin requirements
      To the extent that the daily insulin regimen is simplified, reduction in total daily insulin may constitute an added benefit. Furthermore, reduction in insulin requirements reflects graft function. Accordingly, reduction in daily insulin requirements should be measured as a secondary outcome.
    3. Health-related quality of life
      Although successful islet transplantation should have a major impact on quality of life, measuring the perceived positive and negative outcomes of the transplantation regimen, in an open-label trial is quite complex. We recommend that any assessment of subject reported outcome evaluate both the positive and negative aspects of the subject’s experience and that the choice of instrument be discussed with us prior to implementation.

    • E. Data Analysis Plan

    A formal data analysis plan should be submitted to FDA for review, prior to initiation of the study. We recommend the use of composite endpoints that measure glucose metabolic control and the frequency of hypoglycemic events (described above in section IV.D.2.b and c). The primary analyses of all outcomes should be performed on an intent-to-treat (ITT) population. The ITT population should include all enrolled subjects who have received any single component of the transplantation regimen (i.e., attempted transplant) or one dose of an immunosuppressive medication. You should include in the data analysis plan the statistical assumptions, rules for imputation of missing data, and descriptions of how all subjects will be accounted for in the analysis. The data analysis plan should include methodology for analyzing the numerous secondary outcomes, recognizing that most of these are inter-related.

    The primary analysis should be performed at least one year after the last islet cell transplant. The protocol should include measurement of the primary efficacy endpoint(s) and as many of the secondary endpoints as feasible, for at least an additional year (i.e., for at least two years after the final transplant).

    Sponsors who intend to compare their outcomes, and/or supplement their safety databases, with results taken from a meta-analysis of published literature or from other sources (such as CITR) should discuss the suitability of the databases with us prior to initiation of the clinical trial. The statistical approaches to these comparisons should be part of the data analysis plan and should be discussed in advance with us.

    F. Follow-Up

    Long-term follow-up is important to assess the results of islet cell transplantation as completely as possible. However, the limited number of subjects enrolled in a single-arm clinical trial, with a short study duration, and lack of concurrent controls (as described in section IV. A) preclude a formal assessment of the effect of islet cell transplantation on progression of major complications of diabetes (retinopathy, nephropathy, neuropathy and macrovascular events), long-term durability of therapeutic effect, and collection of AEs due to the islet cell product, or the concomitant immunosuppressive regimen such as an increase in malignancies or infections. Nonetheless, such trials should include provisions for long-term monitoring of renal, ophthalmological (e.g., worsening of retinopathy), neurological, and cardiovascular status (coronary artery disease and peripheral artery disease, including foot ulcers and amputations), islet function, and AEs. Accordingly, long-term follow-up should be built into each of these trials and the informed consent document must explain the purpose and expected duration of long-term follow-up observations, and a description of the procedures to be followed (21 CFR 50.25), which should include the timing and location (office visit, telephone contact, etc.) of data collection. Details of long-term follow-up should be discussed with us prior to initiation of pivotal clinical trials.

     

    Footnotes

    http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070342.pdf.
    2 Acceptance criteria means numerical limits, ranges, or other criteria for the tests described (21 CFR 600.3(kk)). See also HRSA regulations at 42 CFR 121.6(c).
    3 Published in the Federal Register of May 25, 2004 (69 FR 29786) available at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2004_registerdocid=fr25my04-11.pdf. Correction published March 24, 2006 (71 FR 14798) available at http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2006_registerdocid=fr24mr06-4.pdf.
    4 This guidance published in February 2007, and reissued with minor revisions in August 2007, available at 

    http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
    Guidances/Tissue/ucm091345.pdf    .
    5 FDA has issued a draft guidance entitled “Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products” dated October 2008 (October 9, 2008, 73 FR 59635), which contains recommendations for developing tests to measure potency in certain products. This draft guidance, when finalized, will represent FDA’s current thinking on this topic.
    6 Currently available at http://www.fda.gov/ohrms/dockets/ac/cber00.htm.
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