Planning and Design of Clinical Trials: 4th Articulation

1. Phase III Trials
   1. The basis of phase III trials can be found in the well-known joke about the famous biostatistician, when asked how his wife was, replied, “Compared to whom?” In medicine field, the question might be, for example, how effective is BCG (an immunotherapy) as a cancer treatment? Compared to what? The Placebo, Chemotherapy, or any other immunotherapy? At what amount of dose, and for what kind and type of cancer? Phase III clinical trials are designed to answer questions like these.
   2. A phase III trial or comparative clinical trial is a planned experiment on human subjects involving two or more treatments in which the primary purpose is to determine the relative merits of the treatments. It is undertaken after the treatment has successfully passed a phase II trial. Comparative clinical trials have elicited great interest and discussion ever since they were introduced in the 1930s by A.B. Hill. Very often they are referred to as the clinical trials. The objectives of comparative clinical trial differ according to what one means by evaluating the relative effectiveness of the treatments. The primary objective may be the selection of the best treatment for future use in patients. It may to estimate the effectiveness of each treatment with some degree of precision. Or, the objective can be twofold, to select the best treatment and to estimate the treatment effect. If the primary aim is to select the best treatment, then some type of sequential plan will be appropriate in which the decision to continue the study at any stage is determined by the results accumulated to that stage. As soon as it is clear which treatment is best for patients, the study will be stopped, even though at that point it may be that, only rather non-accurate estimates of the effectiveness of each and every treatment can be deciphered. If there is a combined aim of selecting the best treatment and learning something about each, a sufficient number of patients should be entered on each treatment so that effectiveness can be estimated with a small amount of precision. Additional patients might be needed to satisfy the further selection requirement. It is implicit that for such a trial it should be ethically justifiable to continue even after sufficient data have been collected to permit a decision about the best treatment. For each particular trial, the objectives need careful consideration, and clinicians should be aware if the types of study implied by a different choice of objectives. It usually is desirable to consult a statistician concerning determination of sample size and stopping rules for the study.
   3. Phase III trials demand very careful planning. Loose plans and loose methods give loose results that may be misleading. In the following, some general guidelines are offered are offered for planning and designing phase III trials.

1. Consideration in Planning

No complete, or completely satisfactory, list of considerations can yet be given. The following are a few important points.

1.                                                               i.      Time for Planning.
   1. Several months to a year should be allowed for drawing up the rules and regulations, or the document specifying the objective of the trial and the plan for carrying it out. If the trial involves more than one institution, a longer planning time (a year or more) should be allowed.
   2.                                                             ii.      Number of Treatments Involved.
      1. The number of treatments involved in a phase III trial are closely related to the number of patients per year that can be expected to enter in a particular study. In order to guarantee enough number of the patients in each and every group’s treatment, a clinical trial should involve a small number of treatments for differentiating.
      2.                                                           iii.      Duration of the Trial.
         1. The estimated duration of a trial includes the period for entry of patients and the follow-up period for the observation of response and survival. George and Desu (1974) derive the necessary duration of a clinical trial based in the assumptions that patients enter the trial according to a Poisson process and the survival time (or time to failure) is distributed exponentially. No rules are available for general cases. However, if a clinical trial extends over a long period of time, it is likely that other treatments will appear as candidates for comparison. In practice, clinical trials extending longer than five years must be thoroughly justified.
         2.                                                           iv.      Comparability of Patients.
            1. The comparative clinical trial should be planned so that the only reasonable explanation for a difference between treatment groups is a result of the treatments. Patients must be comparable with respect to prognostic factors; otherwise, the results will very likely be misleading. A technique to achieve comparability of patients at the time of entry is formal randomisation. However, randomisation does not guarantee that patients in treatment groups will be comparable with respect to all prognostic factors. Although adjustments can often be made in analysis, comparability needs to be checked & assured before the analysis is done.

             

          

       

    

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