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Abstract：
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 beta 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.
摘要：
已经考虑了证明猪胰岛移植临床试验合理的临床前疗效和并发症数据。与临床胰岛移植有关，临床前数据应在猪至糖尿病非人灵长类动物(NHP)模型中获得.鉴于难以长期维持免疫抑制的NHP，在以下建议方面必须允许灵活性。如果在具有证实的糖尿病的NHP中的八个连续实验中的五个符合以下准则,则临床前试验将被认为是成功的。1.NHP的空腹和非空腹血糖水平维持在约<150mg/dl（>8.3mmol/l）和<200mg/dl（11.1mmol/l），分别,在整个6个月的随访期间（最好在1个或2个NHP中观察到12个月）。2.成人或胎儿/新生猪胰岛移植后，正常血糖状态发展后，不需要或需要大量减少的外源性胰岛素（成人可能需要大约前4周，胎儿/新生儿胰岛需要12周，分别)，除了在特殊情况下，临时情况。3.序贯静脉内葡萄糖耐量试验[在移植后1、3、6(和12)个月]或精氨酸刺激试验已经表明,在NHHC-肽不存在显著响应的情况下,对猪C-肽形式的葡萄糖的显著响应。4.尸检后对天然胰腺（如果存在）的组织学研究表明没有或只有极少量的胰岛素阳性β细胞，肝脏或胰岛移植的其他部位的组织学检查表明有多个活的胰岛素阳性细胞。5.许多或严重的危及生命的并发症与移植程序无关，免疫抑制方案，耐受性诱导方案，或胰岛的封装。受者NHP不需要持续免疫抑制治疗的临床前试验(例如，当封装的胰岛已被移植时）可能被认为是可接受的，作为临床试验的基础，对第（1）和（2）点的要求稍低，但预计会提供证据表明，第(3)点，(4),（5）已经实现。
