Sample size interim analysis

Timing of any interim analysis Reason for sample size Power of clinical study Level of significance Criteria for termination of study Procedure for missing and imused data Reporting procedures for deviations from statistical plan... 

Also, the analysis plan should identify the statistical methods that will be used and how hypotheses will be tested (e.g., a p value cutoff or a confidence interval for the difference that excludes 0). And the plan should prespecify whether interim analyses are planned, indicate how issues of multiple testing will be addressed, and predefine any subgroup analyses that will be conducted. Finally, the analysis plan should include the results of power and sample size calculations. 

It is not a requirement that a trial must have an interim analysis, either for efficacy or for futility. In most long-term trials, however, where there is the opportunity for an interim evaluation then it may be something worth putting in place. The interim can involve only efficacy, only futility, or both and may indeed involve some other things as well, such as a re-evaluation of sample size (see Section 8.5.3). 

Finally, it is, in principal, possible to increase the sample size based on the observed treatment difference at an interim stage without affecting the type I error, but great care needs to be taken with regard to dealing with this statistically. Evidence to date suggests that such procedures offer no real advantages over and above a standard interim analysis plan. 

The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect. The protocol for the study and report of results should describe the study design precisely for example, duration of treatment periods, whether treatments are parallel, sequential, or crossover, and whether the sample size is predetermined or based upon some interim analysis. Generally, the following types of control are recognized ... 

In the fixed sample clinical trial approach, one analysis is performed once all of the data have been collected. The chosen nominal significance level (the Type I error rate) will have been stated in the study protocol and/or the statistical analysis plan. This value is likely to be 0.05 As we have seen, declaring a finding statistically significant is typically done at the 5% p-level. In a group sequential clinical trial, the plan is to conduct at least one interim analysis and possibly several of them. This procedure will also be discussed in the trial s study protocol and/or the statistical analysis plan. For example, suppose the plan is to perform a maximum of five analyses (the fifth would have been the only analysis conducted had the trial adopted a fixed sample approach), and it is planned to enroll 1,000 subjects in the trial. The first interim analysis would be conducted after data had been collected for the first fifth of the total sample size, i.e., after 200 subjects. If this analysis provided compelling evidence to terminate the trial, it would be terminated at that point. If compelling evidence to terminate the trial was not obtained, the trial would proceed to the point where two-fifths of the total sample size had been recruited, at which point the second interim analysis would be conducted. All of the accumulated data collected to this point, i.e., the data from all 400 subjects, would be used in this analysis. 

The code will be broken and data will be analyzed when the 12-mo follow-up has been completed for all patients. At that time, DHA therapy will be offered to all patients who desire to receive it. Clinical and laboratory studies will be monitored by an independent data and safety monitoring committee. This committee will also perform an interim analysis when 30 patients have completed assessment and has permission to terminate the study if there are significant favorable findings or unanticipated adverse outcomes. A determination of statistical power indicates that this sample size is sufficient to detect a major effect (0.862 standard deviations). With a more modest effect of 25%, however, the statistical power diminishes to 60%. The study has been approved by the Institutional Review Board at the Johns Hopkins Medical Institutions and is supported by a research grant from the Office of Orphan Products Development at the Food and Drug Administration. Fifty-two patients are enrolled in the study at this time. The code has not yet been broken. No adverse effects attributable to the medication have been observed. 

In the example trial in Table 7.1, the first interim analysis occurs after 60 events. Here, we observe 33 events in 812 patient-years of follow-up in the control group and 27 events in 817 patient-years of follow-up in the treatment group. The predictive probability of showing Cl < 1.3 at the maximum sample size is 0.920 > 0.05, so e trial does not stop for futility. The entire 99% Cl was < 1.8, therefore, the trial transitions to Stage 2, and tire next interim analysis occurs after 100 additional events are observed (Table 7.1 "Look 2"). 

More recently, there has been interest in adaptive designs where the sample size and number of events are increased based on an unblinded look at interim analysis results. For example, a trial might be initially sized based on the number of MACE outcomes needed to demonstrate noninferiority however, if superiority appears likely based on the conditional power available at the time of an interim analysis, the number of needed MACE outcomes and the sample size could be increased. Such adaptive designs require special statistical analyses to protect the alpha level and special provisions to minimize operational bias (FDA 2010). This approach reduces the risks to participants (and to the sponsor) associated with initiating a large superiority trial up-front, when there is limited information about the compound. 

Ref. (61)]. The interim results confirmed the feasibility and safety of using E2F-I decoy. Analysis of the secondary endpoints using quantitative coronary angiography and three-dimensional intravascular ultrasound demonstrated increased patency and adaptive vessel remodeling characterized by reduction in neointimal size and volume in the treated group one year after treatment, leading to 40% reduction in critical stenosis. These results will now need to be confirmed in adequately sampled and powered phase III studies in patients with coronary and peripheral vessel disease in order to further... 

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