Randomized controlled trials are the gold standard to investigate efficacy and safety of new treatments. In certain settings, however, randomizing patients to control may be difficult for ethical or feasibility reasons. Borrowing strength using relevant individual patient data on control from external trials or real‐world data (RWD) sources may then allow us to reduce, or even eliminate, the concurrent control group. Naive direct use of external control data is not valid due to differences in patient characteristics and other confounding factors. Instead, we suggest the rigorous application of meta‐analytic and propensity score methods to use external controls in a principled way. We illustrate these methods with two case studies: (i) a single‐arm trial in a rare cancer disease, using propensity score matching to construct an external control from RWD; (ii) a randomized trial in children with multiple sclerosis, borrowing strength from past trials using a Bayesian meta‐analytic approach.

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Parameters of calcium and phosphate metabolism were measured in 27 patients with mild renal failure [glomerular filtration rate (GFR) 40-90 ml/min], 12 patients with moderate renal failure (GFR 20-39 ml/min) and in 12 healthy subjects. GFR was determined by technetium-99m diethylenetriamine pentaacetic acid clearance. Intact parathyroid hormone (PTH) was measured by a sensitive immunochemiluminometric assay and somatomedin-C was determined by radioimmunoassay. Both 1,25-dihydroxyvitamin D [1,25(OH)₂D] and vitamin-D-binding protein were measured allowing calculation of the free 1,25(OH)₂D index. By linear regression and multivariate analysis, PTH was negatively and independently correlated with GFR, plasma bicarbonate and 25-hydroxyvitamin D [25(OH)D] while free 1,25(OH)₂D was positively correlated with GFR. Increased PTH secretion and reductions in 1,25(OH)₂D were present in mild renal failure patients before any changes in plasma calcium, phosphate and bicarbonate were noted. Plasma alkaline phosphatase was significantly higher in mild chronic renal failure patients compared to normal subjects, possibly indicating early effects of the secondary hyperparathyroidism on the skeleton. Somatomedin-C did not correlate with the free 1,25(OH)₂D index or a measure of 1,25(OH)₂D production. It is concluded that the secondary hyperparathyroidism which occurs very early in the onset of chronic renal failure may be due to a reduction in the circulating concentration of 1,25(OH)₂D consequent upon the renal failure. Low plasma bicarbonate and 25(OH)D also appear to be determinants of a raised PTH concentration. The compensatory increase in PTH presumably maintains extracellular calcium and phosphate levels constant but with possible deleterious effects on the skeleton.