General Description and Objectives

The term Phase III trial is synonymous with a prospective comparison under randomized treatment assignment [alternately called a randomized controlled trial or randomized clinical trial (RCT)] of two or more treatment regimens, conducted for the purpose of establishing which is superior or, in some cases, to establish equivalence (in the sense that any difference in outcome is smaller than that considered clinically material) between different treatment regimens. Thus, two key features that distinguish RCTs are the inclusion of a concurrent control group and the use of randomization to assign treatment. The main purpose of concurrently evaluating individuals receiving the standard and test treatment(s) is to eliminate temporal trends in diagnosis, characterization of the disease, and ancillary care that would likely be present in any comparison with a historical control group. Concurrent evaluation also provides implicit control over the commonly seen phenomenon of research participation itself having a positive effect on outcomes, regardless of the type of intervention. Randomization, which disassociates treatment assignment from any and all extraneous factors on the part of the patient or the physician, is the fundamental means by which bias is removed from measures of treatment effect.

The obvious alternative to randomization is a nonran-domized comparative trial, but this design is generally insufficient for definitive evaluation of treatments for the purpose of choosing one over another. While differences in characteristics between treatment groups can be addressed to various degrees in other ways, typically by comparing "like with like" through matching, stratification into homogeneous groups, or statistical modeling or adjustment, only randomization will reliably eliminate bias in treatment comparisons. Furthermore, it is often not the known potential confounding factors that we must concern ourselves with, but rather unknown or uncollected factors, where these methods are not relevant. Nonetheless, primarily due to ethical concerns, some advocate relying on observational studies with reference to historical experience, coupled with the use of statistical methods to account for potential confounding of treatment effects and other factors, to evaluate new treatments.47,48 Numerous problems with the validity of historically controlled comparative studies have been demonstrated specifically in cancer research, including temporal changes in disease definition,49,50 data quality issues,51 diagnostic bias in assessing treatment response,25 and out-of-date historical control comparisons that tend to inflate effects for new therapies.23 The RCT in and of itself represents a significant medical research advance, and, as the recognized gold standard evaluative tool in therapy development, is integral to the evidence-based medicine paradigm.

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