Letters

Use of randomisation in early clinical trials

Theobald's trial in 1936 incorporated some aspects of randomisation

Memories of why allocation by random sampling numbers was used

Theobald's trial in 1936 incorporated some aspects of randomisation

EDITORThe issue of 31 October marking 50 years of the randomised controlled trial, with historical accounts on trial methodology, made me look up the trial undertaken by Theobald. He studied the combined effect of calcium, vitamin A, and vitamin C supplementation on toxaemia in 100 pregnant women, apparently using true individual randomisation. ^{1 2} This was in 1936, a decade before the streptomycin trial.³

Although not all aspects of the randomisation procedure are entirely clear from Theobald's report, ^{1 2} he was obviously a thoughtful researcher. He provided evidence that the groups had similar age and parity distributions, had a statistician (E S Pearson) to assess the extent to which his results (that symptoms of toxaemia were less common in the treatment group) could have arisen by chance, and even used blinding of the primary outcome assessors. Despite these facts Theobald's trial seems to be little cited in the literature.

Another London trial is interesting from a methodological point of view. During 1938-9 the People's League of Health allocated over 5000 pregnant women from 10 hospitals to receive either no supplement or a supplement containing calcium, vitamin A, and vitamin C as well as other substances. ^{4 5} The trial was an enormous achievement, not only because of its size but also because of its methodological standard.⁵

The People's League of Health trial used alternate allocation rather than true randomisation, although the team concerned must have known about Theobald's trial: its medical secretary (W C W Nixon) was affiliated to St Mary Abbots Hospital, where Theobald had conducted his trial. Further, in his report Theobald had foreshadowed the People's League of Health trial by stating that "experiments conducted on these lines would show to what degree the different protective substances are associated with toxaemia symptoms" and that he published the results "in the hope that further experiments on a larger scale will be conducted elsewhere."

We can only speculate why the People's League of Health team did not adopt Theobald's idea of implementing true randomisation; feasibility could be one reason. Perhaps someone knows the relation between these trials and their conduct.

Sjúrur F Olsen, Senior epidemiologist. 
Maternal Nutrition Group of the Danish Epidemiology Science Centre, Statens Serum Institut, DK-2300 Copenhagen C, Denmark sfo{at}ssi.dk

Memories of why allocation by random sampling numbers was used

EDITORI am one of the last surviving members of the Medical Research Council's streptomycin in tuberculosis trials committee.¹ My recollection is that the committee was aware of the difficulty of avoiding selection bias in allocation to test and control groups in a trial in which blinding was impossible. Because of this we readily accepted the procedure of allocation by random sampling numbers advocated by Bradford Hill and hoped that it would prove practicable.

I was familiar with Bradford Hill's work on the design of clinical trials, both from a course of lectures that he gave in the late 1930s and from reading his book published in 1937.² In 1944, during war service in Egypt, I had designed and carried out a double blind placebo controlled study of the effects of sulphonamides in bacillary dysentery; selection bias had been eliminated by the formulation of test and control medications as indistinguishable suspensions, identified by letters.³ The streptomycin trial could not be blind, either to observers or to patients, and the more complicated method of allocation by random sampling numbers seemed to offer the most promising way of minimising bias.

We welcomed the opportunity to design an objective study of the clinical effects of a promising but unproved antimycobacterial agent in a manner ethically acceptable in the existing circumstances. We realised that it was the decisionfor which we had no responsibility but regarded as wise and far sightedto devote the limited supply then available to such a study that provided this probably unique opportunity.

J G Scadding, Emeritus professor of medicine. 
Imperial College School of Medicine National Heart and Lung Institute, London SW3 6LY