Computing exact one-sided confidence limits for treatment effect in clinical trials

ABSTRACT

One standard summary of a clinical trial is a confidence limit for the effect of the treatment. Unfortunately, standard approximate limits may have poor frequentist properties, even for quite large sample sizes. It has been known since Buehler (1957) that an imperfect confidence limit can be adjusted to have exact coverage. These “tight” limits are the gold standard frequentist confidence limit. Computing tight limits requires exact calculation of certain tail probabilities and optimisation of potentially erratic functions of the nuisance parameter. Naive implementation is both computationally unreliable and highly burdensome, and perhaps explains why they are not in common use. For clinical trials however, where the data and parameter have dimension two, the difficulties can be fully surmounted. This paper brings together several results in the area and applies them to simple two dimensional problems. It is shown how to reduce the computational burden by an order of magnitude. Difficulties with the optimisation reliability are mitigated by applying two different computational strategies, which tend to break down under different conditions, and taking the less stringent of the two computed limits. This paper specifically develops limits for the relative risk in a clinical trial, but it should be clear to the reader that the method extends to arbitrary measures of treatment effect without essential modification.

Keywords:

• Buehler bounds
• Tight upper limits

Mathematics Subject Classification:

• 62F03