The history and development of N-of-1 trials

‘Trials of therapy’, in which physicians ‘try out’ treatments and assess patients’ responses, are long-established, common elements of routine medical practice. Because ‘trials of therapy’ are usually informal, they may only be reported if treatments are associated with dramatic changes in a patient’s condition – whether by improvement or deterioration. Our understanding of bias suggests that informal ‘trials of therapy’ – comparisons of patients’ condition before and after treatment – do not provide a trustworthy basis for inferring treatment effects. More sophisticated comparisons are usually needed: for example, comparing a patient’s responses when treatments are given or withheld (‘crossed over’) and conducting formal assessment of outcomes. In 1676, Richard Wiseman (a surgeon to King Charles II) reported an unplanned experiment. He had prescribed a pair of laced stockings for a patient suffering from leg oedema. The stockings had reduced the oedema to the extent that the patient ‘was able to walk to his closet, and take the air in his coach, and was well pleased with them’. However, someone suggested to the patient that the stockings might do him harm and persuaded him to remove them. His legs swelled up, he became confined to bed again and developed leg ulcers. Dr Wiseman waited six weeks for the ulcers to heal, restored the laced stockings, with the result that the patient recovered. A century after Wiseman’s crude crossover trial of laced stockings, Caleb Parry, a doctor in Bath, England, published a more formal, planned use of between two and six crossover periods of variable duration in 13 patients, to compare the purgative effects of three varieties of rhubarb. Parry was unable to find any advantage of the more costly Turkish rhubarb compared with English rhubarb. Parry’s ‘trials of therapy’ were important in having used at least two crossovers, but he took no steps to ensure that his andhis patients’ assessments of the treatment effects were not influenced by his or the patients’ knowledgeof the type of rhubarb being given.Fourteen years later, also in Bath, JohnHaygarth compared the effects on rheumatism of a metal ‘tractor’ with a matched wooden (placebo) tractor. This demonstrated that the assumed treatment effects of the metal tractor resulted from patients’ imagination. Haygarth’s study made clear that informal ‘trials of therapy’ can be plagued by false positives (due to placebo effects, physicians’ and patients’ desires to please, the pre-existing expectations of both parties and natural history). And they can also result in false negatives (patients destined to deteriorate and the intervention resulting in them remaining stable). Although more than a century passed after Haygarth before Paul Martini set out principles for designing unbiased crossover trials in his 69-page book, it appears that it was not until 1953 that serious scientific consideration was given to how controlled trials in individual patients could complement traditional parallel group trials. Hogben and Sim recognised that: