Novel Tech Ethics, Faculty of Medicine, Dalhousie University, P.O. Box 15000, 1379 Seymour Street Halifax, NS, Canada.
Curr Gene Ther. 2017;17(4):309-319. doi: 10.2174/1566523217666171121165935.
A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for patients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and efficacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are themselves poorly designed - as a result of which the quality of pre-clinical evidence is deficient - then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validity, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically examine the pre-clinical evidence used to justify the first-inhuman Phase 1 CRISPR gene editing cancer trial in the United States using these tools. We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient.
在美国，一项针对黑色素瘤、滑膜肉瘤和多发性骨髓瘤患者的首创性 CRISPR 基因编辑人体第一阶段临床试验前景乐观，这表明基因编辑工具可能有助于治疗人类疾病。然而，人体第一阶段临床试验面临的一个首要伦理挑战是，根据临床前研究获得的安全性和疗效数据，何时可以在伦理上接受启动此类试验。如果指导试验设计的临床前研究本身设计不佳——从而导致临床前证据质量不足——那么临床研究的科学有效性的伦理要求可能得不到满足。反过来，这可能意味着第一阶段临床试验不安全，试验参与者将面临风险而没有潜在的益处。为了帮助赞助商、研究人员、临床研究人员和审查人员确定何时在伦理上可以接受启动首创性 CRISPR 基因编辑人体第一阶段临床试验，已经开发了结构化流程来评估和最小化临床前和临床研究之间的转化距离。这些流程提请注意内部有效性、结构有效性和外部有效性的各种特征。此外，还需要批判性地评估支持证据的可信度，特别要注意乐观偏差、财务利益冲突和发表偏倚。我们使用这些工具批判性地检查了用于证明美国首例人体第一阶段 CRISPR 基因编辑癌症试验的临床前证据。我们的结论是，拟议的试验不能满足科学有效性的伦理要求，因为用于告知试验设计的支持性临床前证据不足。
