Overall success rate of a safe and efficacious drug: Results using six phase 1 designs, each followed by standard phase 2 and 3 designs.

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.