Randomisation and alternation in clinical trials

 In early clinical trials patients were allocated to treatment and control groups by alternation, i.e. patients were assigned to the treatment group and control group in a strict order. The advantage with this method was that it produced groups with equal size. The two groups would also be fairly compared if the order of the patients included in the trial was random. However, the group allocation for a patient was predictable, which could potentially introduce selection bias into the trial's outcome through differential invitations to participate. The only way to avoid this issue was, of course, to make the group assignment concealed, which necessitated a non-systematic group assignment sequence.

D'Arcy Hart (1) describes the development with two trials from the 1940s. The first one investigating the effects of patulin (a mycotoxin) on the common cold in 1943-1944 with strict alternation. The second one, having a randomised group assignment, investigating the effects of streptomycin on pulmonary tuberculosis in 1947-1948. Since then, a randomised and concealed group assignment is considered an essential feature of modern randomised trials that have been discussed in depth (2).

With alternation groups sizes are exactly balanced because if a patient declines to participate in the trial, the next patient takes the declining patient's place in the group assignment scheme. In contrast, randomised groups can have different size. More importantly, randomisation is not performed to get treatment groups that are balanced in terms of patient characteristics. It is performed to guarantee that any residual imbalance has a known origin of chance, rather than being caused by possibly biased investigator decisions.

Furthermore, alternation can lead to a treatment effect estimate whose standard error is underestimated because of selection bias. Randomisation does thus not estimate individual outcome variance more precisely than alternation, but it makes the treatment effect estimate and its standard error credible.

References

1. D'Arcy Hart P. A change in scientific approach: from alternation to randomised allocation in clinical trials in the 1940s. BMJ. 1999 Aug 28;319(7209):572-3. doi: 10.1136/bmj.319.7209.572. PMID: 10463905; PMCID: PMC1116443.

2. Yoshioka A. Use of randomisation in the Medical Research Council's clinical trial of streptomycin in pulmonary tuberculosis in the 1940s. BMJ. 1998 Oct 31;317(7167):1220-3. doi: 10.1136/bmj.317.7167.1220. PMID: 9794865; PMCID: PMC1114162.

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