Interim analysis design

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 ... 

Clinical trials, with almost no exception, are longitudinal (Chow and Liu, 2004). This means that data are accumulated sequentially over time. From the perspective outlined so far in the book, the statistical analysis takes place once the number of subjects stated in the study protocol have been enrolled, randomized, and completed their participation in the trial. This approach can be called the Fixed design or fixed sample design approach. Another design of interest in clinical trials is the group sequential design, in which interim analysis plays a crucial role. 

Hwang, I.K. and Lan, K.K.G., 2006, Interim analysis and adaptive design in clinical trials. In Buncher, C.R. and Tsay, J-Y. (Eds), Statistics in the pharmaceutical industry, 3rd Edition, Chapman Hall/CRC, 245-284. 

Administrative interim analysis should provide feedback on whether the study is being executed as designed and whether the data are being thoroughly and accurately collected. This is a gauge of the conduct of the study, not of the results. Randomization codes need not be broken. 

Spectacularly effective drugs may achieve a very small a at the time of the interim analysis. Stopping the trial by reason of the unethical basis for treating the patients with anything else is a rare and pleasant event for the clinical trialist. However, in that spectacular success, the pharmaceutical physician should ask whether a minimization design would have achieved the same thing with even fewer patients, and thus actually feel chastened. 

One type of flexible design is the group sequential design (23). Such a design typically includes one or more preplanned interim analyses. Based on the results of the interim analysis, a preplanned action is taken. Most commonly these actions include ... 

Group sequential designs facilitate interim analyses. As the name connotes, these analyses are performed during the conduct of a smdy, i.e., before the study has gone to the full term as outlined in its study protocol. Several interim analyses may be performed during an ongoing clinical trial at various pre-identified points. Each interim analysis conducted utilizes all of the data that have been collected to the point when a... 

Group sequential designs facilitate interim analyses being performed during the conduct of a clinical trial. Each interim analysis that is performed utilizes all of the data that have been collected to the point when a given analysis is conducted. 

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. 

Trial design (choice of control group, procedures for avoiding bias, criteria for interim analysis, etc.)... 

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