Matched eyes from a natural history study as an external control group in LHON

Leber's Hereditary Optic Neuropathy (LHON) is an orphan mitochondrial disease resulting in loss of vision due to optic nerve atrophy. The efficacy of idebenone, a synthetic analogue of coenzyme Q10, in LHON has been demonstrated in a randomized controlled trial (Klopstock et al., 2011) and in a case series comparing treated and untreated patients (Carelli et al., 2011); further placebo-controlled trials in LHON are therefore considered unethical. However, inability to control bias due to the lack of randomization, blinding and comparability of the control group is the major and well-recognized limitation of externally controlled open-label studies (OLS). More persuasive and potentially less biased approaches include selection of patient data from a control group, as similar as possible to the OLS population and in which observations use timing and methodology similar to those used in the OLS, prior to performing comparative analyses.