Clinical trials interim analyses

Moreover, in a subseqnent interim analysis of fractnres in a large, ongoing, controlled clinical trial, preliminary analysis are reported as being consistent with the resnlts from the ADOPT-study (http //www.fda.gOv/MEDWATCH/SAFETY/2007/ Avandia GSK Ltr.pdf). 

Censoring in clinical trials usually occurs because the patient is still alive at the end of the period of follow-up. In the above example, if this were the only cause of censoring then all the censored observations would be equal to 24 months. There are, however, other ways in which censoring can occur, such as lost to follow-up or withdrawal. These can sometimes raise difficulties and we will return to discuss the issues in a later section. Also, at an interim analysis the period of follow-up for the patients still alive in the trial would be variable and this would produce a whole range of censored event times our methodology needs to be able to cope with this. 

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. 

Several interim analyses may be performed during an ongoing clinical trial at various preidentified points. Each interim analysis conducted utilizes all of the data that have been collected to date. The rationale for this approach is that this strategy may reveal compelling evidence that the clinical trial should be stopped at the time of a particular interim analysis because there is already compelling evidence that the drug is effective or that it is toxic. This particular interim analysis could be conducted some considerable time before the trial would have otherwise been completed. 

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. 

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. 

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. 

It is not the purpose of this chapter to delve into the mechanics of statistics. However, a few comments about the relationships between values for a at the stage of an interim and complete statistical analysis of a clinical trial may be in order. There are several statistical points of view on this subject, and... 

Any interim analysis that is not planned appropriately (with or without the consequences of stopping the trial early) may flaw the results of a trial and possibly weaken confidence in the conclusions drawn. Therefore, such analyses should be avoided. If unplanned interim analysis is conducted, the clinical study report should explain why it was necessary and the degree to which blindness had to be broken, and provide an assessment of the potential magnitude of bias introduced and the impact on the interpretation of the results. (ICH, E9, 4.5)... 

Mettler, L. Audebert, A. Lehmann-Willenbrock, E. Jacobs, V.R. Schive, K. Prospective clinical trial of spraygel as a barrier to adhesion formation an interim analysis. J. Am. Assoc. Gynecol. Laparosc. 2003, 10 (3), 339-344. 

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. 

An Interim Analysis of Phase I Clinical Trial of MCC-465, a Doxorubicin (DXR) Encapsulated in PEG-immunoliposome, in Patients with Metastatic Stomach Cancer... 

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