Sequential trial design

Figure 9.2 The Armitage ( sequential analysis ) clinical trial design...

Looked at in terms of the number of trials that are run by the pharmaceutical industry, sequential trials are relatively unimportant. However, since such trials are often run where the number of patients needed is suspected to be great, they are relatively more important in terms of numbers of patients and also of cost. Nevertheless, it remains true that there are many indications in drug development where such trials are never or rarely used and I think it is only fair that I should warn the reader that in all my time in the pharmaceutical industry I never designed or analysed one myself. But since leaving... 

Whitehead J (1997) The Design and Analysis of Sequential Trials, revised 2nd edition. John Wiley Sons, Ltd, Chichester. 

Boundary approach. An approach to running and analysing sequential trials whereby a statistic describing the cumulative difference between treatments is plotted against a statistic which describes the amount of evidence accumulated to date and the trial is stopped if one of the pre-specified boundaries of the design is crossed. 

Ochiai T, Hamasaki T, Evans SR, Asakura K, Ohno Y (2016) Group-sequential three-arm noninferiority clinical trial designs. J Biopharm Stat [Epub ahead of print]... 

Estimates of service life are usually made either by natural or simulated trials or, most commonly, by accelerated tests with extrapolation to predict performance at longer times under less severe conditions. An alternative approach is to subject the product to environmental exposures which equate to the whole design life, and then to assess performance by real or simulated service tests (the end performance assessment). The exposures usually have to involve accelerated procedures and can be composed of several environmental agents applied simultaneously or sequentially. 

Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika 1977 64 191-99. 

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. 

By its nature, therefore, the group sequential design involves the possibility of multiple testing. In this example it is possible that five analyses could be conducted on data collected in this clinical trial. As discussed in Section 7.10, there is an inherent problem with multiple testing. As more tests are performed, it becomes increasingly likely that a Type I error will occur, i.e., that a result will erroneously be declared as statistically significant. As also noted at that point, however, the problem can be addressed completely satisfactorily by taking appropriate statistical care. 

Whitehead Design and Analysis of Sequential Clinical Trials, Revised Second Edition... 

Gordon PH, Cheung YK, Mitsumoto H, Levin B (2005) Novel phase II design for clinical trials of ALS using selection paradigm and group sequential analysis. Amyotroph Lateral Scler 6 14—15. 

Interim analyses can reduce the power of statistical significance tests to a serious degree if they are scheduled to occur more than, say, about four times in a trial. Such sequential designs recognise the reality of medical practice and provide a reasonable balance between statistical, medical and ethical needs. It is a necessity to have expert statistical advice when undertaking such trials poorly designed and executed studies cannot be salvaged after the event. 

Fixed-sample size and sequential designs SENSITIVITY OF TRIALS... 

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