When I was in medical school, I had the good fortune to be able to cross-register into Harvard Law to take an amazing course on Food & Drug Law. It really opened my eyes to how things worked at the FDA and was a great backdrop for the advanced pharmacology course I took the following month. As part of that course, I researched and wrote a paper on the ethics of human research and learned a great deal about the origins and evolution of clinical trials in drug discovery. As I found the historical origins to be rather interesting, I thought I would share some of that here.
Bringing a drug to market is well understood to be a lengthy and challenging process. One of the reasons for this is that due to certain inherent biases and confounding events, it is often very difficult to ascertain whether or not a given intervention truly caused the observed effect. For these reasons, the FDA currently requires that “substantial evidence” of efficacy from “adequate and well-controlled trials” is required prior to the approval of any New Drug Application (NDA) (see 21 CFR 314.126). The phrase “adequate and well-controlled” trials is generally interpreted to mean that more than one trial has been conducted with concordant and statistically significant results or that a single trial has achieved the statistical standard of two positive trials (P < 0.00125). [1]
Since its introduction, the modern randomized controlled trial (RCT) has become widely recognized as the “gold standard” of clinical research. The RCT is described as “the best method available to confirm the value or to test the efficacy of a treatment, to prevent the propagation of worthless treatments, or to document harm caused by a conventionally and widely used therapy.” [2] The use of randomization in treatment assignment in these trials can be controversial and may appear to be counter to the aforementioned ethical standards. The justification of randomization is based on the assumption of clinical equipoise – a “state of genuine uncertainty” on the part of the medical community “regarding the comparative therapeutic merits of each arm in a trial.” [1] However, should equipoise cease to exist, the medical community is ethically obliged to provide the superior therapy. This ethical mandate provides the basis for the early termination of clinical trials.
The first truly modern randomized controlled trial occurred in 1948 with the British Medical Research Council’s study of “Streptomycin in the treatment of pulmonary tuberculosis“. This trial established the necessary principles for the conduct of large-scale patient randomization; in addition, it formulated “guidelines for the administration of an experimental therapy and the objective evaluation of outcomes.” [3] Prior to this study, controlled clinical trials were the exception, with most published medical data being limited to observations and statements of opinion. [4] However, there are a few notable exceptions worth mentioning including Lind’s study of scurvy in British sailors (1753) [5] the results of which were largely ignored by the British Admiralty for over 40 years; Louis’ study of bloodletting in pneumonia (1798); [6] and Waterhouse’s study of the smallpox vaccine in orphan teenage boys (1800). [7,8]
The practice of randomization of research subjects did not originate with the aforementioned British Medical Research Council study, but its origins are not much older. The first published randomization in a controlled trial was actually performed not on patients but on potatoes by Fisher and Mackenzie [9] in 1923 as part of an agricultural study on crop protection. Amberson [10] has been credited with the first use of randomization in a study of human patients in 1931. In a small study of tuberculosis therapy in 24 patients, he used a coin toss to make treatment assignments.
The British Medical Research Council study heralded the beginning of the modern era of clinical research. In the decade that followed this landmark study, the number of publications describing the use of RCTs grew rapidly. In addition, an analysis performed by Max [4] in 2002 of published review articles regarding trial methods during the 1950s noted that the methods in practice during the 1950s were remarkably similar to current practices in trial administration.
One of the main distinctions between clinical trials in the 1950s and the current era, is that it was not until the mid-1960s that any significant discussion was had regarding the prospective and continuing review of research by individuals not intimately involved with the conduct of the trial in order to ensure patient safety and study validity. These ethical considerations will be the subject of a separate post.
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[1] Fisher L, Klibaner M. “Regulatory issues for Data and Safety Monitoring Committees.” Am Heart J 2001;141;536-541.
[2] Bobbio M. “To stop or not stop a clinical tiral: that is the problem.” Ital Heart J 2000:1(12):821-823.
[3] Califf RM. “Large Clinical Trials: Clinical Research Institutes.” Principles and Practice of Clinical Research
[4] Max MB. “Small Clinical Trials.” Principles and Practice of Clinical Research
[5] Lind J. A treatise on the scurvy. In three parts. Containing an inquiry into the nature, causes and cure of that disease. Together with a critical and chronological view of what has been published on the subject. London: printed by Sands, Murray, and Cochran for A. Kincaid and A. Donaldson, 1753.
[6] Louis PCA. Researches on the effects of bloodletting in some inflammatory disease, Boston: Hilliard, Gray and Company, 1836.
[7] Waterhouse B. A prospect of exterminating the smallpox: being the history of variolae vaccinae, or kinepox commonly called the cow-pox; as it appeared in England; with an account of a series of innoculations performed for the kinepox, in Massachusetts … (Cambridge, MA). Printed for the author, all at the Cambridge Press, by William Hilliard, and sold by him and the other booksellers in Boston. 1800.
[8] Moore FM. “Zabdiel Boylston and colonial surgery. American surgery and public health in the early 18th century.” Bull Am Coll Surg, 1983;68(5):13-17.
[9] Fisher R.A., Mackenzie W.A., “Studies of crop variation. II. The manorial response of different potato varieties. “ J Agric Sci 1923;13:1315.
[10] Amberson JB, McMahon BT, Pinner M. “A clinical trial of sanocrysin in pulmonary tuberculosis.” American Review of Tuberculosis 1931;24:401-435.
