Sectio N 314.166 Of

In Chapter 2 we introduced some sources of bias and variation that can occur during the conduct of clinical trials. The control of bias and variability is extremely important to ensure the integrity of clinical trials. In comparative clinical trials, randomization is usually used to control conscious or unconscious bias in the allocation of patients to treatment groups. The purpose of randomization is not only to generate comparable groups of patients who have similar characteristics but also to enable valid statistical tests for clinical evaluation of the study medicine.

The concept of randomization was first introduced in clinical research in the early 1930s for a study of sanocrysin in the treatment of patients with pulmonary tuberculosis (Amberson et al., 1931). However, the principle of randomization was not implemented in clinical trials until mid-1940s by the British Medical Research Council under the influence of Sir Austin Bradford Hill (1948). Since then there have been tremendous debates over the use of randomization in clinical research (e.g., see Feinstein, 1977, 1989). The primary concern is that it is not ethical for the patient not to know which treatment he or she receives, especially when one of the treatments is a placebo. However, it was not realized that before a clinical trial is conducted, no one can be 100% sure that the active treatment is indeed effective and safe for the indicated disease compared to the placebo. For many drug products it is not uncommon that the active treatment has inferior efficacy and safety than the placebo. One typical example would be the CAST study discussed in previous chapters. For another example, if randomization is not employed for comparing a surgical procedure with chemotherapy in treatment of patients with a certain cancer, then the so-called operable patients with good prognoses will more likely be assigned to surgery, while the chemotherapy will be given, as is usual, to the inoperable patients with poor prognoses.

Design and Analysis of Clinical Trials: Concepts and Methodologies, Second Edition By Shein-Chung Chow and Jen-pei Liu

ISBN 0-471-24985-8 Copyright © 2004 John Wiley & Sons, Inc.

The surgical treatment would have yielded the positive results even though the surgery was not performed at all.

The use of randomization can avoid subjective assignment of treatments to patients who participate in clinical trials. Its advantage can be best illustrated by clinical studies concerning the treatment of gastric freezing for patients with peptic ulcer conducted in the 1960s (Miao, 1977; Sackett, 1989). In these studies, the treatment of gastric freezing was applied to tens of thousands of patients with peptic ulcer in a nonrandom fashion. These studies showed that the gastric freezing might be a promising therapy for the disease. However, it only took one randomized trial with 160 patients, half to the real or sham freezing, to conclusively demonstrate that the treatment of gastric freezing is in fact ineffective for the treatment of peptic ulcer. Therefore, Section 314.166 of the CFR requires that the method for patient treatment assignment should be described in some detail in the study protocol and report. It is recommended that for a concurrent controlled study, treatment assignment of patients be done by randomization. It should be noted that randomization in clinical trials consists of (1) random selection of a representative sample from a targeted patient population and (2) random assignment of patients in order to study the medicines.

To remove the potential bias that might occur when there are inequalities between treatment groups (e.g., demographic details or prognostic variables) allocated to different treatment groups, the use of randomization with blocking and/or stratification, if necessary, is helpful. Lachin (1988a, 1988b) provides a comprehensive summary of the various randomization models. The concept behind these randomization models allows useful randomization methods to be employed such as the complete randomization, the permuted-block randomization, and the adaptive randomization. Randomization plays an important role for the generalization of the observed clinical trials. Therefore it is recommended that a set of standard operating procedures (SOP) for the implementation of randomization be developed when conducting clinical trials. In many clinical trials bias often occurs due to preconceived ideas or perceptions acquired during the study by (1) the investigator and supporting staff who might influence reporting response to therapy or adverse events and (2) the patient who might influence compliance, cooperation, or provision of information.

In clinical trials, in addition to randomization, the technique of blinding is usually employed to avoid the risk of personal bias in comparing treatments. Basically there are several different types of blinding commonly used in clinical trials. These blindings include open label (or unblinding), single blinding, double blinding, and triple blinding. An open label study indicates that both the patient and the investigator know to which treatment group the patient is assigned, while a single blinding is referred to as that when the investigator knows but the patient does not. For a double blinding, neither the investigator nor the patient knows to which treatment group the patient is assigned. A triple blinding is an extension of the double blinding in which those monitoring outcome are unaware of treatment assignment. In practice, randomization and blinding are important to the success of clinical trials. Randomization and blinding can not only help to avoid bias but also to control variability, and consequently to achieve the desired accuracy and reliability of clinical trials.

The remainder of this chapter is organized as follows. In the next section, we introduce various randomization models. Section 4.3 covers the different randomization methods. In Section 4.4 we provide a commonly employed approach for the implementation of randomization in the pharmaceutical industry. The issue regarding the generalization of controlled randomized trials is discussed in Section 4.5. The concept for the use of blinding in clinical trials is addressed in Section 4.6. A brief discussion is given in Section 4.7.

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