Introduction

In clinical research, the ultimate goal of a clinical trial is to evaluate the effect (e.g., efficacy and safety) of a test treatment as compared to a control (e.g., a placebo control, a standard therapy, or an active control agent). To ensure the success of a clinical trial, a well-designed study protocol is essential. A protocol is a plan that details how a clinical trial is to be carried out and how the data are to be collected and analyzed. It is an extremely critical and the most important document in clinical trials, since it ensures the quality and integrity of the clinical investigation in terms of its planning, execution, conduct, and the analysis of the data of clinical trials. During the conduct of a clinical trial, adherence to the protocol is crucial. Any protocol deviations and/or violations may introduce bias and variation to the data collected from the trial. Consequently, the conclusion drawn based on the analysis results of the data may not be reliable and hence may be biased or misleading. For marketing approval of a new drug product, the United States Food and Drug Administration (FDA) requires that at least two adequate and well-controlled clinical trials be conducted to provide substantial evidence regarding the effectiveness of the drug product under investigation (FDA, 1988). However, under certain circumstances, the FDA Modernization Act (FDAMA) of 1997 includes a provision (Section 115 of FDAMA) to allow data from a single adequate and well-controlled clinical trial to establish effectiveness for risk/benefit assessment of drug and biological candidates for approval. The FDA indicates that substantial evidence regarding the effectiveness and safety of the drug product under investigation can only be provided through the conduct of adequate and well-controlled clinical studies. According to the FDA 1988 guideline for Format and Content of the Clinical and Statistical Sections of New Drug Applications, an adequate and well-controlled study is defined as a study that meets the characteristics of the following: (i) objectives, (ii) methods of analysis, (iii) design, (iv) selection of subjects, (v) assignment of subjects, (vi) participants of studies, (vii) assessment of responses, and (viii) assessment of effect. In the study protocol, it is essential to clearly state the study objectives of the study. Specific hypotheses that reflect the study objectives should be provided in the study protocol. The study design must be valid in order to provide

a fair and unbiased assessment of the treatment effect as compared to a control. Target patient population should be defined through the inclusion/exclusion criteria to assure the disease conditions under study. Randomization procedures must be employed to minimize potential bias and to ensure the comparability between treatment groups. Criteria for assessment of the response should be pre-defined and reliable. Appropriate statistical methods should be employed for assessment of the effect. Procedures such as blinding for minimization of bias should be employed to maintain the validity and integrity of the trial.