Introduction to Clinical Trials
The evolution of the modern clinical trial dates back at least to the eighteenth century [1, 2]. Lind, in his classical study on board the Salisbury, evaluated six treatments for scurvy in 12 patients. One of the two who was given oranges and lemons recov
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Introduction to Clinical Trials
The evolution of the modern clinical trial dates back at least to the eighteenth century [1, 2]. Lind, in his classical study on board the Salisbury, evaluated six treatments for scurvy in 12 patients. One of the two who was given oranges and lemons recovered quickly and was fit for duty after 6 days. The second was the best recovered of the others and was assigned the role of nurse to the remaining ten patients. Several other comparative studies were also conducted in the eighteenth and nineteenth centuries. The comparison groups comprised literature controls, other historical controls, and concurrent controls [2]. The concept of randomization was introduced by Fisher and applied in agricultural research in 1926 [3]. Probably the first clinical trial that used a form of random assignment of participants to study groups was reported in 1931 by Amberson et al. [4]. After careful matching of 24 patients with pulmonary tuberculosis into comparable groups of 12 each, a flip of a coin determined which group received sanocrysin, a gold compound commonly used at that time. The British Medical Research Council trial of streptomycin in patients with tuberculosis, reported in 1948, used random numbers in the allocation of individual participants to experimental and control groups [5, 6]. The principle of blinding was also introduced in the trial by Amberson et al. [4]. The participants were not aware of whether they received intravenous injections of sanocrysin or distilled water. In a trial of cold vaccines in 1938, Diehl and coworkers [7] referred to the saline solution given to the subjects in the control group as a placebo. One of the early trials from the National Cancer Institute of the National Institutes of Health in 1960 randomly assigned patients with leukemia to either 6-azauracil or placebo. No treatment benefit was observed in this double-blind trial [8]. In the past several decades, the randomized clinical trial has emerged as the preferred method in the evaluation of medical interventions. Techniques of implementation and special methods of analysis have been developed during this period.
© Springer International Publishing Switzerland 2015 L.M. Friedman et al., Fundamentals of Clinical Trials, DOI 10.1007/978-3-319-18539-2_1
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1 Introduction to Clinical Trials
Many of the principles have their origins in work by Hill [9–12]. For a brief history of key developments in clinical trials, see Chalmers [13]. The original authors of this book have spent their careers at the U.S. National Institutes of Health, in particular, the National Heart, Lung, and Blood Institute, and/or academia. The two new authors have been academically based throughout their careers. Therefore, many of the examples reflect these experiences. We also cite papers which review the history of clinical trials development at the NIH [14–18]. The purpose of this chapter is to define clinical trials, review the need for them, discuss timing and phasing of clinical trials, and present an outline of a study p
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