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3. The effect on the primary endpoint plainly failed to meet the pre-specified statistical criteria, but is very close. Is very close good enough? Could other findings buttress the result? And is an effect of the magnitude seen a meaningful benefit at all?
5. The other effectiveness findings (symptomatic benefits) are generally favorable but, with one exception (the Borg score), are potentially contaminated by unblinding because of injection site pain. And even the Borg and exercise test could be unblinded for the patient. Could some of them be persuasive anyway (e.g., rate of new appearance of a problem not reported at baseline?) and how does one deal with the high level of multiplicity?
6. What does the increasing dose mean: disturbing evidence of tolerance to whatever effect the drug has, or alternatively, an inevitable consequence of a design that allowed dose increases if patients were still symptomatic, which, of course, all were and would be expected to be, despite treatment. The increase in dose on placebo was about twice that on treprostinil (? evidence of effect)
The review shows that assigning a low rank to selected WD’s [e.g., (1) those who died or were terminated in < 100 days, (2) those who received Flolan within one month of DC, (3) those who received Flolan up to 100 days] eliminated statistical significance
Similarly, we are skeptical about subsets (low baseline) as a way to conclude there is an effect, but if the overall result is positive (a debatable question) there may be some legitimacy to seeing whether the effect seems more meaningful in a subset. Consistency of such a finding in the two studies could support such an approach
|Author: Sandra Benton|