Assuming these values, the definitive sample size for the study was set at 604 subjects, randomised as described above.
Our pilot data support the idea that minimal or no adjustments to the definitive sample size calculation are required for losses to follow-up.
We planned a priori to transition directly from our pilot RCT to a definitive RCT if feasibility was established, with the pilot event rate used to inform the definitive sample size estimation.
Interim analysis after inclusion of 53 patients (50%) will provide the definitive sample size, which will be calculated based on the observed number of complications in the EBD group.
The definitive sample size will be determined similar to the provisional sample size, again using a relative decrease of 50% in the proportion of complications unless the absolute decrease drops below 20%, which is defined as the lowest absolute decrease with clinical relevance.
Bearing this in mind, the distribution shown in the column "Definitive Sample" in Table 2 was obtained, this distribution was used for the study.
This approach is, of course, limited by the particular features of the reference mutation data set employed, e.g. inclusion of cell lines and tissues, over- and under- representation of cancer types, the lack of a definitive sample denominator for many mutations, and redundancy of samples, etc.
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Quantifying the current state of knowledge will help to inform dose selection decisions when evidence generation in the target population is deemed unethical or definitive sample sizes are not feasible, as may be the case, for example, when diseases are rare.
