include plans for auxiliary treatments and progression to other treatments in the face of disease progression.
In a phase III confirmatory study (see below), the ideal is typically an effectiveness study of a treatment strategy: effectiveness because it is the impact of a treatment on the population and a treatment strategy because the initial prescribed treatment may greatly affect the concomitant treatments and follow-on treatments administered to patients. However, true effectiveness can never be tested in an unbiased fashion because the trial setting itself is artificial and because observational studies are always subject to unmeasured bias. Phase III studies should be much closer to an effectiveness study than would be the phase II studies that might use surrogate biomarkers as a primary outcome in a subpopulation of the patients that might ultimately receive an approved treatment.
Whether the primary goal of a clinical trial is effectiveness or efficacy, the scientific validity of the comparison of the new treatment to some standard depends on the comparability of the groups that receive the experimental and control treatments. Randomization of patients to two or more treatment groups is the primary tool to ensure the comparability of samples, at least on average. Hence, it is of utmost importance that the data from each clinical trial be analyzed consistent with the intent-to-treat principle, which dictates that each subject’s data be included in the treatment group to which he or she is randomized. This approach is clearly in keeping with an evaluation of the effectiveness of a treatment strategy, but even when evaluation of efficacy is the goal, the clinical trial should ideally be designed in such a way that all randomized patients will contribute to the estimate of treatment efficacy. However, in limited situations, it might be judged acceptable to evaluate efficacy in a modified intent-to-treat subgroup of randomized patients defined on the basis of measurements made prior to randomization and ascertained in an unbiased fashion for each treatment group. In this setting, safety would still be evaluated in patients who are not in the subgroup.
In neither effectiveness nor efficacy studies would an analysis based on a compliant or per-protocol analysis population (defined as patients who adhered strictly to the prescribed dose, frequency, and duration of the assigned treatments) be considered a scientifically rigorous assessment of the treatment. Instead, when the efficacy of the treatment in a compliant population is of interest, one needs to find a way to randomize only those patients who can tolerate the treatment and who will adhere to the protocol (see below).