The introduction of randomized controlled experiments in agriculture in the 1920s and 1930s sometimes involved designing studies to make more than one comparison in the same experiment. Partly because of the different circumstances in medicine, such studies appear to have been rare in medicine at that time. An apparent early example of such a factorial trial was reported by Wyckoff and his colleagues (1930), who evaluated the effects of digitalis in pneumonia on patients already allocated alternately to anti-pneumococcus serum. Such factorial designs, simultaneously testing two or more treatments within the same investigation, can be a more economic form of research than organising several independent controlled trials. In the Wyckoff trial, however, no factorial analysis was conducted and it seems likely that the design chosen was simply expedient in that all patients were already divided into serum and non-serum groups, and this was the most efficient way of maximising patient numbers for the digitalis trial.
In 1946, Wilson, Pollock and Harris reported a factorial trial in a paper published in The Lancet, which also served as a report to the Medical Research Council. They had formed four comparison groups from the start using a sample of patients with infective hepatitis, one of the most common major medical problems affecting the armed forces operating in the Mediterranean at that time (Cohen 1944). There was interest in the potential of sulphur-containing amino acids (such as methionine and cysteine) in altering the clinical course of ‘infective’ hepatitis in animals and possibly humans (Beattie and Marshall 1944; Himsworth and Glynn 1944; Peters et al. 1944; Wilson et al 1945), and varying opinions about the impact of dietary fat. The hepatitis/jaundice link with disturbed fat metabolism caused most clinicians to recommend low fat diets (although it would have been equally logical to increase fat content to compensate for its metabolic deficiencies).
Wilson, Pollock and Harris tested the effects on the disease both of supplementary cysteine (which had been assessed in an earlier study by the same authors (1945) and had just become more available from the wartime Ministry of Supply), and of dietary fat reduction. They first allocated alternate patients to cysteine-supplemented and cysteine non-supplemented groups; then patients within each of these two groups were allocated alternately to high and low fat diets. There is no indication in the paper that the authors had considered that there might an interaction between cysteine and dietary fat, another main reason for using factorial design trials, and so the results of dietary fat and cysteine supplementation are presented separately. In fact the reason that fat reduction was evaluated as well as supplementation with cysteine appears to have been that it was difficult to maintain calorie input in patients who were often anorexic using low fat diets that were difficult to provide, unpalatable and probably unnecessary. These patients, whilst averse to greasy foods, were not so reluctant (in wartime-rationed Britain) to consume eggs, butter, cheese, milk and cream, which were rich in another sulphur-rich amino acid: methionine. It made sense to try to sort the matter out.
A modest benefit of cysteine was suggested by the data; but the authors judged this to have been a reflection of a higher number of relapses in controls, and “likely to have arisen merely by chance”. Their conclusions might have differed had they used more modern statistical techniques: the results actually indicate that chance alone was unlikely to have resulted in this difference (2/52 versus 10/51, relative risk = 0.2, 95% confidence limits: 0.05, 0.85, generating a continuity-adjusted p value of 0.029). There was no hint, however, that fat reduction had any effect. This is probably just as well because the observation would have been confounded by a substantial difference in the total calorific value of the diets (high fat: 3056 cals/day; low fat: 2025 cals/day), and possibly also with the dietary methionine differences, which were correlated with them. Furthermore, the results should be interpreted with caution because the sequential alternation probably increased the risk that the allocation schedule would not be adhered to strictly, a danger that eventually led to the adoption of precautions to conceal allocation schedules (MRC 1948).
Factorial trials were soon used to good effect to explore two or more independent topics in one experiment as a measure of economy and administrative ease. They were used in further studies of the effects of treatments for hepatitis (Chalmers et al. 1955; Sackett 2008), and in trying to sort out the mess of multiple treatment options for patients with gastric ulcers (Doll and Pygott 1952, Doll 1964). Not only could they be used to study alternative therapies, but they were sometimes suitable (size and statistical power permitting) for investigating completely independent clinical problems (see, for example, Physicians Health Study Group 1989; Hennekens et al. 1996). It also became clear that factorial design trials constituted a powerful way of examining combination therapies and synergistic or antagonistic interactions between treatment combinations (ISIS-2 Collaborative Group 1988; MRC Vitamin Study Group 1991)
The complexities that factorial trials can create are not inconsiderable: assessing statistical power, especially if studying interactions; matching separate inclusion/exclusion criteria; dealing with separate side effects, compliance differences and cross-over problems; and coping with trial stopping decisions. However, all these issues were absent in this early example of a factorial trial. It was an affordable, sensible opportunity to examine two ‘separate’ clinical management issues in one series of patients. How ‘simple’ medical research once was……!
Beattie J, Marshall J (1944). Methionine in the treatment of liver damage. Nature 153:525.
Cohen H (1944). Recent advances in medical treatment. Practitioner 153:193-205.
Chalmers TC, Eckhardt RD, Reynolds WE, Cigarroa JG, Deane N, Reifenstein RW, Smith CW, Davidson CS (1955). The treatment of acute infectious hepatitis. Controlled studies of the effects of diet, rest, and physical reconditioning on the acute course of the disease and on the incidence of relapses and residual abnormalities. Journal of Clinical Investigation 34: 1163-1235.
Doll R (1964). Medical treatment of gastric ulcers. Scottish Medical Journal 9:183-196.
Doll R (1991). Development of controlled trials in preventive and therapeutic medicine. Journal of Biosocial Science 23:365-378.
Doll R, Pygott F (1952). Factors influencing the rate of healing of gastric ulcers: admission to hospital, phenobarbitone, and ascorbic acid. Lancet 1: 171-175.
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R (1996). Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine 334:1145-9.
Himsworth HP, Glynn LE (1944). Toxipathic and trophopathic hepatitis. Lancet 1:457-461.
ISIS-2 Collaborative Group (1988). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-360.
Medical Research Council (1948b). Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation. BMJ 2:769-782.
MRC Vitamin Study Group (1991). Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338:131-137.
Peters RA, Thompson RHS, King AJ, Williams DI, Nicoll CS (1944). Sulphur-containing amino-acids and jaundice. Nature 153:773.
Physicians’ Health Study Research Group (1989). Final report on the aspirin component of the ongoing Physicians’ Health Study. New England Journal of Medicine 321:129-35.
Sackett DL (2008). A 1955 clinical trial report that changed my career. JLL Bulletin: Commentaries on the history of treatment evaluation (http://www.jameslindlibrary.org/articles/a-1955-clinical-trial-report-that-changed-my-career/)
Wilson C, Pollock MR, Harris AD (1945). Therapeutic trial of methionine in infective hepatitis. BMJ 1:399-401.
Wyckoff J, Du Bois EF, Woodruff IO (1930). The therapeutic value of digitalis in pneumonia. JAMA 95:1243-1249.