Clinical Trials Come of Age
My interest in science was always essentially limited to the study of principles … That I have published so little is due to this same circumstance, as the great need to grasp principles has caused me to spend most of my time on fruitless pursuits.
–Albert Einstein
After a certain high level of technical skill is achieved, science and art tend to coalesce in esthetics, plasticity, and form. The greatest scientists are always artists as well.
–Albert Einstein
Many authors have recounted the long and colorful history of clinical trials, usually starting with James Lind’s evaluation of citrus fruit (i.e., lemons, oranges) and other possible treatments of scurvy [i.e., cider, vinegar, seawater, oil of vitriol (dilute sulfuric acid) or a control diet] in British sailors in 1747. Although his study was open-label, underpowered (n = 2 per group), and not randomized, the effect he observed was dramatic and years later led to the British Navy issuing limes to sailors to prevent scurvy (which was also the origin of the British sailors being called “limeys”).
The development of clinical trials has progressed through many stages since then, particularly during the second half of the 20th century. The development of modern clinical trials began with the first randomized human clinical trial in 1948, with a trial conducted by the United Kingdom’s Medical Research Council (Hill 1952). This trial addressed the question of whether streptomycin and bed rest was a better treatment for pulmonary tuberculosis than bed rest alone. The growth of clinical trials since then has been remarkable, and the Cochrane Controlled Trials Register reported over 415,000 trials by 2004 (Cocharne Collaborative 2004). Paul, Seib, and Prescott (2005) state that it took from 1948 to 1969 for the first 1,000 clinical trials to be conducted, but in each year since 2000 (and possibly before), many thousands are conducted. The conclusion is inescapable that the field of clinical trials has achieved a standard over the past two decades that may be described as a “coming of age.”
CRITERIA TO DEFINE A DISCIPLINE’S COMING OF AGE
Seven criteria of a discipline’s maturity are used as the basis for stating that clinical trials have come of age:
An agreed-upon mission and approach
A generally accepted methodology for planning and conducting research
Practitioners who identify themselves as part of a group (i.e., clinical trialists, methodologists, or practitioners)
Established standards that influence or even control the practice of the discipline
Training and certification programs for professionals entering the field plus professional association(s)
Identified career opportunities and paths for advancement
External recognition and/or acceptance of the discipline
This chapter briefly summarizes each of these criteria but focuses primarily on the second, clinical trial methodologies.
The Mission for Clinical Trials
Clinical trialists have the mission of designing and conducting clinical trials and analyzing and interpreting their results at a high standard. The practice of involving a team of professionals in a clinical trial rather than just the primary investigator has
expanded over the past few decades in trials sponsored by the industry, the government, and academicians. Relatively few trials today involve only a single investigator, although it is possible for a single person to plan, conduct, analyze, and interpret small size clinical trials entirely on his or her own. The primary approach used to design, conduct, analyze, and interpret results of clinical trials is that of a team, consisting of any number of individuals representing some (or all) of the disciplines listed in Table 84.1.
expanded over the past few decades in trials sponsored by the industry, the government, and academicians. Relatively few trials today involve only a single investigator, although it is possible for a single person to plan, conduct, analyze, and interpret small size clinical trials entirely on his or her own. The primary approach used to design, conduct, analyze, and interpret results of clinical trials is that of a team, consisting of any number of individuals representing some (or all) of the disciplines listed in Table 84.1.
Table 84.1 Individuals who are often part of a clinical teama | ||||||||||||||||||||||||||||||||||||||||||||||||
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Clinical Trial Methodologies
Prior to 1970, few authors attempted to summarize the state of knowledge of clinical trials in monographs, although a number of review articles were written. The field was discussed most often and most clearly by statisticians, many of who were (rightfully at that time) trying to achieve a greater and more appropriate role for statistics in clinical trials. The classic textbook of clinical statistics, Principles of Medical Statistics, was first published by Austin Bradford Hill in 1937. It has had a few title changes and the 12th edition was published in 1991 (Hill and Hill 1991). During the early 1980s, a number of books on clinical trial methodologies were written (Pocock 1983; Friedman, Furburg, and DeMets 1998). They were primarily statistical texts, and the statistical approach they promoted was particularly important for persuading physicians and others that statisticians must be involved in virtually all clinical trials and at every stage—not just after the trial is completed.
Until the 1980s, it was common practice (and still occurs in some places today) for a clinician to design and conduct a clinical trial and then, after the trial was completed, to turn over the data to a statistician for data processing, analysis, and possibly interpretation as well. At that stage (i.e., after a clinical trial is completed), no statistician could resurrect a seriously flawed trial. The need for input by statisticians prior to a trial as well as afterwards was increasingly accepted by the medical community during the 1970s and 1980s. The pendulum was starting to swing, however, towards statisticians’ controlling the design and interpretation of data from clinical trials. By the early 1980s, some clinicians were feeling that the field of clinical trial methodology was becoming too statistically oriented and controlled.
In response to the need for clinically oriented textbooks on clinical trials, a series of three books on clinical trial methodology (Spilker 1984; Spilker 1986; Spilker 1987) was written to present a clinical orientation to clinical trial design, conduct, interpretation, and management. These books did not include the statistical approaches or formulae used in previous books on clinical trial methodologies. Many statistical concepts were described, however, and the essential requirement and value of statistical input was stressed throughout each of these three books.
The first book of this trilogy, Guide to Clinical Studies and Developing Protocols (Spilker 1984) focused on the clinical protocol; the second book, Guide to Clinical Interpretation of Data (Spilker 1986), suggested that the role of statisticians includes that of analyzing data from clinical trials and that the role of clinicians includes that of interpreting clinical trial data that have been analyzed and also extrapolating the results of the trial further (if appropriate). This book presented and discussed various clinical approaches to interpreting data. The third book in this trilogy [Guide to Planning and Managing Multiple Clinical Studies (Spilker 1987)] described methods and approaches used to plan and oversee large programs of either single-site or multisite trials.
A second edition of these three books combined, updated and expanded them into a single volume of 133 chapters [Guide to Clinical Trials (Spilker 1991)]. This expanded book contains a broad coverage of clinical trial methodology from a clinician’s perspective. It is acknowledged in the book that a statistical text or statistician is also an essential part of the process of planning, conducting and analyzing data from clinical trials. Another general text on clinical trial methodologies was written by Meinert and Tonascia (1986).
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