Challenges in Trial design
As discussed above, the interpretation of the impact of emerging therapies on respiratory function using aggregate data is confounded by phenotypic variability where it may not be possible to determine if a subject is evolving naturally with favorable or unfavorable respiratory function. As well, the age group commonly evaluated combines subjects whose VC may be rising with others whose VC is declining. When true randomization is not possible, attempts to accommodate for this have included propensity matching as in the ataluren study41. However, propensity score matching can only adjust for measured covariates, and one cannot be assured that all confounding factors have been eliminated 52.
Becuase of the somewhat unpredictable evolution of respiratory function in any given individual which may confound study results for a treatment intervention, consideration might be given to an N of 1, crossover design where subjects are compared with themselves under control and experimental conditions and crossed over at intervals from one to the other 53. The duration of recent studies and the suggestion of improvements due to treatment as early as 26 weeks47, indicate that these investigations might lend themselves to such an N of 1 design, e.g. randomization to 6 to 12 months of intervention or placebo, followed by crossover for the remaining 6 to 12 months. Such a design would help address the issues with regard to randomization and phenotypic variability.
Future studies should employ outcome measures which take in to account the dynamic of respiratory function evolution at different ages and which are sensitive to change. A number of parameters should be followed including those which are sensitive to respiratory muscle strength (MIP, SNIP) and absolute VC which, particularly in an N of 1 design, would account for individual variations in age at maximal VC and rate of decline. The utilization and impact of standard therapies must also be considered in fully understanding the effect of emerging therapies.