Confirmatory trials

The number of partidpants must be chosen so that the trial wUl have suflEdent statistical power , particularly in the case of confirmatory trials. As a general prindple, the greater the number of data, the greater the confidence there is in demonstrating that a statistical difierence between two groups exists, or not. However, numbers of participants will be constrained by cost considerations, the availability of suitable subjects and, above all, by the ethical prindple that subjects should not be enrolled in clinical trial unless they add scientific value. 

A confirmatory trial is an adequately controlled trial in which the hypotheses are stated in advance and evaluated. As a rule, confirmatory triab are needed to provide firm evidence of efficacy or safety. ... 

The rationale and design of confirmatory trials nearly always rests on earlier clinical work carried out in a series of exploratory studies. Like all clinical trials, these exploratory studies should have clear and precise objectives. However, in contrast to confirmatory trials, their objectives may not always lead to simple tests of pre-defined hypotheses. ... 

Treatment effects on surrogate endpoints therefore do not necessarily translate into treatment effects on clinical endpoints and the validity of the surrogate depends not only on the variable itself but also on the disease area and the mode of action of the treatment. Establishing new valid surrogates is very difficult. Fleming and DeMets conclude that surrogates are extremely valuable in phase II proof of concept studies but they question their general use in phase III confirmatory trials. 

In general, it is advantageous to demonstrate a lack of sensitivity of the principle trials results to alternative choices of the set of subjects analysed. In confirmatory trials it is usually appropriate to plan to conduct both an analysis of the full analysis set and a per-protocol analysis, so that any differences between them can be the subject of explicit discussion and interpretation. ... 

Having considered these and other issues, what is a suitable dosing regimen for therapeutic exploratory and therapeutic confirmatory trials ... 

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. 

In addition to having an acceptable safety profile, an investigational drug needs to display beneficial therapeutic effects. This takes us into the realm of therapeutic exploratory and therapeutic confirmatory trials. The statistical approaches discussed in this chapter are characteristic of those employed in these trials. 

All of the studies that are performed before a therapeutic confirmatory trial is started collect information that facilitates a logical scientific progression from FTIH studies to the point where the therapeutic confirmatory trial is appropriate. In a real sense, all of these studies, and all of the information gained to date, have had one purpose to allow the primary objective in the therapeutic confirmatory trial to be stated as simply as possible. In this context, the word simple is not pejorative. To the contrary, a primary objective that can be stated simply can be tested simply, i.e., in a straightforward and unambiguous manner. This is a highly desirable attribute in a primary objective. 

By the time a therapeutic confirmatory trial is appropriate, it should be possible to state a single primary objective (or perhaps two if the sponsor really feels that this is appropriate) that is clinically relevant and biologically plausible. One primary objective also means that sample-size estimation can be based on that objective and the associated estimated treatment effect of interest (recall the discussions in Chapter 9). 

Later in the clinical development program to demonstrate that the final commercial formulation to be marketed upon approval is equivalent to the formulation used in confirmatory trials. Issues of mass production and manufacturing scale-up can be relevant here (see Chapter 12). 

If all goes well in the therapeutic confirmatory trials and the drug is approved, successful commercialization of the approved drug has its own demands. Of relevance in this chapter is the sponsor s ability to manufacture sufficient quantities of the drug in a form that can be readily transported from the manufacturing plant to the pharmacy and in a form that demonstrates stability and therefore has a suitably long shelf-life. 

While the nature of the analyses of data from therapeutic confirmatory clinical trials is relatively straightforward compared with those undertaken in earlier stages of clinical development, supreme care should again be taken in all aspects of design, methodology, and analysis, since only then can optimum quality data be used to provide optimum answers to well-constructed research questions. Chapter 10 noted that safety data are typically presented descriptively at this time but that this may change in due course. By the time that therapeutic confirmatory trials are conducted, there should be a small number of precisely asked research questions that address the efficacy of the drug. 

The requirement to show statistical significance in therapeutic confirmatory trials places a certain importance on a priori hypothesis testing. However, as we have seen, there is much more to clinical research than p-values. Piantadosi (2005) commented on this issue as follows ... 

Phase II trials, termed dose finding studies, in a table listing the length of the study period and the number of subjects. Results of the Crixivan trials were compared to other treatments, especially AZT when taken alone. Phase III trials, generally considered key to determining efficacy, are described as confirmatory trials, since Crixivan s early success had put it on an accelerated track. 

A pharmionic program can be implemented to enhance patient adherence, based on the principle that what is measured can be managed what wasn t measured didn t happen . In a confirmatory trial, it is crucial to guarantee that patients get the optimal exposure to the test drug. 

Tight experimental control is an extremely important goal in all experimental trials. Consequently, we talk a lot about how to maximize such control in these trials. However, it is simply a realistic consequence of the way that therapeutic confirmatory trials have to be conducted that the experimental control cannot be quite as tight in these trials as it is in human pharmacology trials and therapeutic exploratory trials. 

The null hypothesis is the crux of hypothesis testing. (It is important to note that the form of the null hypothesis varies in different statistical approaches. As the main type of clinical trial discussed in this book is the therapeutic confirmatory trial, we talk about this first. We then talk briefly about the forms of the null hypothesis that are used in other types of trials in Section 3.10.) As noted earlier, therapeutic confirmatory trials are comparative in nature. We want to evaluate the efficacy of the investi-... 

A common design in therapeutic exploratory and confirmatory trials... 

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