Study protocols sample size estimation

A sample-size estimation must be based on a specific objective in a clinical trial s study protocol. By the time sample-size estimation becomes particularly meaningful, i.e., in later-stage clinical trials designed to demonstrate efficacy, it is a very good idea to have a single objective (the primary objective) and a single... 

Safety analyses are not typically prespecified in the study protocol and/or the study analysis plan. Studies are typically powered on efficacy outcomes (the primary objective in therapeutic confirmatory trials see Chapter 9), and the sample size that results from this sample-size estimation may be considerably smaller than would be needed for a thorough investigation of safety data. 

This sample size estimate would be described in the study protocol in this manner ... 

A certain number of participants need to be recruited for any given trial. In Section 12.2 we discussed sample size estimation, which takes into account a number of considerations that are important not only to the statistician but also to the clinical scientist and the regulator. Once determined, the value produced by this process of estimation is incorporated into the study protocol. 

A revised sample size may then be calculated using suitably modified assumptions, and should be justified and documented in a protocol amendment and in the clinical study report... The potential need for re-estimation of the sample size should be envisaged in the protocol whenever possible. ... 

The rationale supporting use of EDi0 as the benchmark dose is that a 10 percent response is at or just below the limit of sensitivity in most animal studies. Use of the lower confidence limit of the benchmark dose, rather than the best (maximum likelihood) estimate (EDio), as the point of departure accounts for experimental uncertainty the difference between the lower confidence limit and the best estimate does not provide information on the variability of responses in humans. In risk assessments for substances that induce deterministic effects, a dose at which significant effects are not observed is not necessarily a dose that results in no effects in any animals, due to the limited sample size. NOAEL obtained using most study protocols is about the same as an LED10. 

The number of subjects to be recruited for the study should be estimated by considering the standards that must be met. It should be calculated by appropriate methods (see statistical analysis and acceptance criteria below). The number of subjects recruited should always be justified by the sample-size calculation provided in the study protocol. A minimum of 12 subjects is required. 

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