Revisiting clinical trial design – more adaptability in Phase I – III?

Elihu H. Estey, MD, from the Seattle Cancer Care Alliance, Seattle, WA, discusses clinical trial design at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. He points out that for clinical trial coordinators, the aim of Phase I trials is to assess toxicity, while the goal of patients is to achieve a response. Phase I trials typically use a 3 + 3 design, which means that if two of the first three patients receiving a dose show excess toxicity, the dose is never revisited. However, it is clear that things other than the dose determine toxicity, such as age or performance status, which are not currently taken into consideration. Prof. Estey points out that this design is used because it has been used for a long time, and both investigators and pharmaceutical companies are familiar and comfortable with it. Other designs have been studied which monitor both response and toxicity to find the ideal dose, or which account for age and covariants, however these are rarely used. The Phase II design which follows is based on Phase I response rates, but does not account for covariants such as the prognoses of the patients in the trial. Prof. Estey argues that in order to reach Phase III as quickly as possible, Phase I and II are not carried out in the best way, and as a result of this many Phase III trials fail, because not enough has been learned from Phase I and II. He also criticized the design of Phase III studies which compare new drugs to standard of care treatments with equal numbers in both groups, when the majority of patients have entered the clinical trial in the hope of receiving the new drug. He suggests that if the results of the trial appear to be positive, the proportion of newly enrolled patients receiving the new drug should be increased, and that trials should be more adaptive by responding to incoming data.

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