Planning and Design of Clinical Trials- 5th Articulation

1. Phase III Trials
   1. Consideration in Planning
      1.                                                             v.      Treatment Allocation Ratio.
         1. Equal allocation of patients to both the two treatments is a common practice. However, it may be appropriate to allot patients randomly in the ratio of 60:40 or 67:33 (2:1) when comparing a new treatment with an old one or when treatment is much more difficult or expensive to supervise. The chance of detecting the real difference between the two treatments is not reduced much as long as the ratio is not extreme than 2:1 (Peto et al. 1976).
      2.                                                           vi.      Use of a Concurrent or Historical Control Group.
         1. A basic requirement by most clinical trials is the “controls”, which is a group of patients corresponding in characteristics to the especially treated group but is not given the treatment. The issue is whether a concurrent group should be used or whether historical controls suffice. The ethical question is whether it is appropriate to withhold from any patient a treatment that might give him benefit. Of course, the effectiveness of the treatment is not proven; if it were, there would be no need for a trial. On the other hand, the treatment has passed trials of phase I and II, so there must be some basis which is justifying a trial. The severity of the problem depends upon what is at stake. If, for example, the treatment in the trial is for fast relief of a common headache, then the morality of a rigidly controlled trial would not be seriously in doubt. However, it might be quite impossible to withhold, even temporarily, any treatment for a disease (e.g., cancer) in which life or death or serious after effects were at stake. In the other hand, it should be realized that a new treatment is certainly not always the best and by no means free of danger. For example, certain antibiotics and hormones are not always innocuous. Thus, comparative trial must be exhaustively weighed in the balance of ethics, each according to its own circumstances and its own problems.
         2. The use of historical controls has been a debatable subject, especially in clinical trials of cancer. The use of historical controls allows all current patients in the trial to receive the new treatment and results compared with that of patients previously treated with the standard treatment. The major problem with historical control is that one is unable to ensure comparability between the groups of patients and methods of evaluation.
      3.                                                         vii.      Treatment Management.
         1. It is important to manage patients on each treatment regimen in the same manner. Definitions of response and that of toxicity should be exactly the same for patients in each and every treatment group. The decision to remove the patients from a trial should be applied in the same way in each and every treatment group. If some investigators have a preference for one of the treatments so that patients are maintained on it longer or are classified as toxic only when toxicity is very severe, and the results could be biased. On the other hand, patients who are on a treatment known to be more toxic may be more likely to report an adverse effect. One way to avoid physician’s or patient’s potential bias or different managements of treatment is to do a double-blind trial. In a double-blind trial, the treatments are prepared in identical forms so that neither of the patients nor the physicians conducting the trial are aware of which specific treatment is being given. However, double-blind trials can be difficult to organise and less effective than expected in bias reduction. For example, if one wants to compare a chemotherapy with no therapy for leukaemia patients, if the therapy is in tablet form, it would be necessary to give tablets to both sets of patients (dummy tablets to the control group) and to take blood samples for each to measure the white blood cells. This could be troublesome in the case of management of the clinical trials. Also, the physician is aware of the types of toxicity to be expected and can find out, by observing toxicity, which patients are receiving each treatment. In addition, it is difficult to explain a double-blind trial to patient and his family. Therefore a double-blind study should be given careful consideration. In certain cases, they obviously cannot apply, such as for studying surgical procedure or radiation therapies.

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