The differences and overlaps between 'explanatory' and 'pragmatic' controlled trials: a historical perspective

In designing a controlled trial, a potential tension may exist between (1) providing insights into therapeutic mechanisms and (2) guiding decisions about ‘what works’ in everyday practice. In their 1967 paper in the Journal of Chronic Diseases, Schwartz and Lellouch1 designated these aims as ‘explanatory’ and ‘pragmatic’, illustrating the potential tension with the different trial designs needed to assess the effect of an agent hypothesised to increase responsiveness to radiotherapy (a ‘radiosensitiser’) with immediate initiation of radiotherapy in the ‘pragmatic’ design versus a 30-day delay in initiating radiotherapy for the ‘explanatory’ design. This dilemma is manifest in real clinical situations, such as chemotherapy or radiotherapy prior to cancer surgery (‘neoadjuvant therapy’), ‘pre-habilitation’ to prepare patients for joint surgery and whether to use a placebo when comparing two versus four times daily drug dosing.