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首页> 美国卫生研究院文献>Contemporary Clinical Trials Communications >Overall success rate of a safe and efficacious drug: Results using six phase 1 designs each followed by standard phase 2 and 3 designs
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Overall success rate of a safe and efficacious drug: Results using six phase 1 designs each followed by standard phase 2 and 3 designs

机译：一种安全有效的药物的总体成功率：采用六个阶段1设计的结果每个阶段均采用标准阶段2和3设计

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摘要

To evaluate the overall success rate of a new drug, phase 1, 2, and 3 trials were simulated using eight toxicity and two non-decreasing efficacy profiles. Six phase 1 designs including the standard 3 + 3, CCD, BOIN, mTPI, mTPI-2, and CRM were considered with standard phase 2 and 3 designs.Based on our results, phase 1 design recommendations are provided when data informing the general shape of the dose-toxicity curve exist. If a large jump in toxicity between dose levels is expected, the standard 3 + 3 design is recommended; it more often recognized when the MTD was exceeded and had the highest overall success rates. If gradually increasing toxicity is expected, a nonstandard design other than the CRM is recommended. Nonstandard designs were more aggressive in dosing and MTD estimation than the standard 3 + 3 and had higher overall success rates, but the CRM was too aggressive and most frequently overestimated the true MTD. If fairly constant, safe toxicity is expected across dose levels, the BOIN or CRM designs are recommended; they escalated to the highest dose most frequently with superior overall success rates.Without data informing the shape of the dose-toxicity curve, nonstandard phase 1 designs with a modified excessive toxicity rule more easily eliminating unsafe dose levels are recommended. With this modification, MTD overestimation error decreased and overall success rates were similar or higher with nonstandard designs. Among nonstandard designs, the modified CCD and BOIN perform well and are as transparent and simple to implement as the standard 3 + 3 design.
机译：为了评估一种新药的总体成功率，使用8种毒性和2种非递减功效曲线模拟了1、2和3期试验。标准的第二阶段和第三阶段设计考虑了六个第一阶段设计，包括标准的3 + 3，CCD，BOIN，mTPI，mTPI-2和CRM，根据我们的结果，当数据通知总体形状时会提供第一阶段的设计建议存在剂量-毒性曲线。如果预计剂量水平之间的毒性会有较大的跳跃，则建议使用标准3 + 3设计;当超过了MTD且总体成功率最高时，它通常会得到认可。如果预期会逐渐增加毒性，建议使用非CRM的非标准设计。非标准设计在剂量和MTD估算方面比标准3 + 3更积极，并且总体成功率更高，但是CRM过于激进，最经常高估了真实MTD。如果相当恒定，则预期在整个剂量水平上均具有安全毒性，建议使用BOIN或CRM设计；在没有数据说明剂量-毒性曲线的形状的情况下，建议采用非标准的1期设计并修改过量毒性规则，以更轻松地消除不安全的剂量水平。通过此修改，MTD高估错误减少了，并且非标准设计的总体成功率接近或更高。在非标准设计中，修改后的CCD和BOIN性能良好，并且与标准3 + 3设计一样透明且易于实现。

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