Chapter 4: Pre‐clinical efficacy and complication data required to justify a clinical trial

  Pre‐clinical efficacy and complication data required to justify a porcine islet transplantation clinical trial have been considered. To be relevant to clinical islet transplantation, pre‐clinical data should be obtained in a pig‐to‐diabetic non‐human primate (NHP) model. In view of the difficulties of maintaining immunosuppressed NHPs for long periods of time, flexibility must be allowed with regard to the following recommendations. A pre‐clinical trial would be deemed a success if five of eight consecutive experiments in NHPs with proven diabetes meet the following guidelines. 1. The fasting and non‐fasting blood glucose levels have been maintained in the NHP at approximately <150 mg/dl (>8.3 mmol/l) and <200 mg/dl (11.1 mmol/l), respectively, throughout a 6‐month follow‐up period (preferably with observations in one or two NHPs extending to 12 months). 2. After the transplantation of adult or fetal/neonatal pig islets, no or greatly reduced exogenous insulin has been required after the development of a state of normoglycemia (that may take approximately the first 4 weeks for adult and 12 weeks for fetal/neonatal islets, respectively), except under exceptional, temporary circumstances. 3. Sequential intravenous glucose tolerance tests [at 1, 3, 6 (and 12) months post‐transplantation] or arginine stimulation tests have indicated a significant response to glucose in the form of porcine C‐peptide in the absence of a significant response of NHP C‐peptide. 4. Histologic study of the native pancreas (if present) after necropsy indicates no or minimal insulin‐positive β cells, and histologic examination of the liver or other site of islet transplantation indicates multiple viable insulin‐positive cells. 5. Numerous or serious life‐threatening complications have not been associated with the transplantation procedure, immunosuppressive regimen, tolerance‐inducing regimen, or encapsulation of the islets. Pre‐clinical trials in which the recipient NHPs do not require continuing immunosuppressive therapy (e.g., when encapsulated islets have been transplanted) may possibly be considered acceptable as a basis for a clinical trial with slightly less stringent requirements with regard to points (1) and (2), but would be expected to provide evidence that points (3), (4), and (5) had been achieved. Table of Contents•  Introduction •  Induction of diabetes in the non‐human primate potential recipient •  Porcine islet transplantation •  Immunotherapeutic protocol •  Determination of success of islet transplantation    Specific tests    Necropsy    Need for re‐transplantation    Post‐transplant hypoglycemic episodes•  Conclusions