What are the appropriate methodologies for evaluating seizures in an open-label study with a small number of subjects (N) on the active drug and repeated seizure data for each subject over time? In the feeder/double-blind RCT study, it was a 1:1 randomization to active and placebo with a small N and repeated measures. I struggle to make sense of the open-label seizure data as there isn’t a proper comparison group, but can we borrow data from the double-blind part of the study to help with the situation? Many thanks.
This is an excellent question. There is a separate issue about the choice of statistical model (I prefer an ordinal longitudinal model with flexible nonlinear adjustment for baseline seizure history). What’s really needed is a validation study where for each of 50 patients we have self-reported seizures and expert adjudicated seizure frequency, for comparison.
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Thank you, Prof. Harrell. Good point about seizure validation for self-reported data - this aspect seems lacking and needs more work in epilepsy research. Regarding the analysis of open-label seizure data, are you saying that it is reasonable to borrow data from the double-blind/feeder study to enable a proper comparison, as follows?
- stack data for the two studies where the data while-on-placebo are treated as one group and the data for while-on-active (which includes both the feeder and open-label studies) are treated as the active group
- analyze the data longitudinally using an ordinal approach with flexible nonlinear baseline seizure adjustment, to compare the active group to placebo
Many thanks - this is helpful! I worked through the examples in the referenced link, but am unsure as to how to implement this for the repeated seizure counts where the control arm from the double-blind/feeder study is used as historical control. Are there additional references/tutorials available on this?
Not that I know of other than the links that are provided in the article.
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