Decision Making and Problem Solving

haematologica | 2009; 94(10) | 1435 | The standard phase III trial These trials typically randomize approximately 400 patients between two therapies. This relatively large number is required to detect relatively small improvements with a false positive rate less than 5% (p<0.05) and a false negative rate less than 20% (80% power). For example, the trials in references 1-3 targeted increases in median event-free survival (EFS) or survival of 6-12 months, in 2-year EFS or survival of from 10% to 20% and in complete remission (CR) rate from 50% to 65%. Consider the relevance of a 6-month improvement in survival to an otherwise healthy 65-year old man with untreated acute myeloid leukemia (AML). Such a patient might expect to live another 15 years if he did not have AML but only another one half-year if he is randomized to a standard treatment arm. In such a case, he only retains 0.5/15 (3%) of his normally remaining life expectancy. If he is randomized to the investigational arm and it is successful, he gains another half-year and now retains 1/15 (7%) of his life expectancy. While statistically significant, I doubt many patients would consider this result medically significant. Hence, the targeted improvement does not reflect clinical reality. The choice of a false positive rate of 0.05 but a false negative rate of 0.20 implies a preference for more protection against a false positive than a false negative result. This is quite sensible when satisfactory treatment exists for the disease in question, and hence, replacement of this standard with a falsely positive new therapy is particularly undesirable. However, because there is no satisfactory treatment for most patients with AML, the medical risk of a false positive is much less. Indeed, the near universal choice of p=0.05 and power=80%, regardless of the disease in question, ignores the reality that diseases vary considerably in curability. Consequently, phase III AML trials should perhaps seek more clinically meaningful improvements and permit higher p values. Although this formulation would result in loss of power to detect relatively small advances, I question whether leukemia therapeutics advances in such small increments. In particular, it would appear that quantum therapeutic advances