Study Design in Osteoporosis: A European Perspective

Abstract

The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate. Rather, studies of superiority, equivalence, or non-inferiority have been recommended. Such studies require very large sample sizes, and the burden of osteoporotic fracture in a trial setting is substantially increased. Studies of equivalence cannot be unambiguously interpreted because the variance in effect of active comparator agents is too large in osteoporosis. If fracture studies are required by regulatory agencies, there is still a requirement for placebo-controlled studies, although perhaps of shorter duration than demanded at

Comment on Putting evidence-based medicine into clinical practice: comparing anti-resorptive agents for the treatment of osteoporosis

“…The publication by Wehren et al 1 used the results of our systematic reviews 2 to make an adjusted indirect comparison of the relative antifracture efficacy of antiresorptive agents 3 . This method compares the relative efficacy of two treatments by using the relative risks of each therapy compared to controls derived from individual meta-analyses.…”

“…Because inferences about efficacy from indirect comparisons are inevitably weak 3 , our summary paper in Endocrine Reviews cautioned readers against using our results to make comparisons of treatment effects 2 . We stated our view that head-to-head comparisons are necessary for generating reliable estimates of comparable drug impact.…”

“…The authors of the Letter have received grants, honoraria and consultancies from several pharmaceutical companies -the original systematic reviews of osteoporosis therapies 2 …”

“…We acknowledge, as stated in the paper, that the technique of adjusted indirect comparison has important limitations and that head-tohead trials with fracture outcomes would be the optimal way to assess relative anti-fracture efficacy of osteoporosis treatments 1 . Head-to-head trials would require very large numbers of subjects; indeed, Kanis and colleagues estimated that 25 000 to 150 000 participants per group would be needed to show a difference between an agent that produced a 60% reduction and one that showed a 50% reduction in fracture risk 2 . To determine that drugs are clinically equivalent (that is, that they differ by only a medically insignificant amount) also requires large sample sizes; otherwise, the risk of type II error (concluding that no difference exists between agents when one does, in fact, exist) is substantial.…”

“…To determine that drugs are clinically equivalent (that is, that they differ by only a medically insignificant amount) also requires large sample sizes; otherwise, the risk of type II error (concluding that no difference exists between agents when one does, in fact, exist) is substantial. Furthermore, because any flaw in execution of such a study would bias results toward a conclusion of equivalence 2 , methodological rigor would need to be extreme. It was recently observed that such a head-tohead trial 'may be a waste of time and resources' 3 .…”