A Randomized, Controlled Trial Comparing Tearcare® and Cyclosporine Ophthalmic Emulsion for the Treatment of Dry Eye Disease (SAHARA) [Response To Letter]

A Randomized, Controlled Trial Comparing Tearcare ® and Cyclosporine Ophthalmic Emulsion for the Treatment of Dry Eye Disease (SAHARA)".Most of the comments seem to be criticism of our statistical design and analysis; these are addressed in the order raised below.The first point concerns the hierarchical testing of the two primary endpoints, tear break-up time (TBUT), and Ocular Surface Disease Index (OSDI).Hierarchical testing using the fixed sequence method (ie, testing the second null hypothesis or endpoint is dependent on rejection of the first null hypothesis) is an accepted and standard method to control for multiplicity, the inflation of a Type 1 error rate due to multiple hypotheses. 1 Chaurasiya et al suggest that this methodology could "introduce bias and limit the interpretation of results".While they do not suggest a specific alternative, they do cite a paper by Huque and Alosh describing a flexible fixed sequence method, the chief advantage being that it allows testing of an endpoint even when a previously tested endpoint was not statistically significant by taking into account correlation between the endpoints to minimize the impact of multiplicity adjustments. 2We appreciate this suggestion, however if we had included this method a priori in our statistical analysis plan, there would be no difference in our reported results or conclusions for our primary outcomes.The first primary outcome variable tested, the difference between groups in TBUT, was in fact, highly significant (p=0.0006), and it is worth noting that the difference between groups for the second primary outcome, OSDI, did not approach statistical significance (p=0.9843).The second point raises concerns about the adequateness of the sample size and the fact that the SAHARA sample size was based on TBUT and not also considering OSDI.This is a reasonable point although ICH E9 states that sample size is usually determined by the primary objective of the trial. 3As TBUT was our first primary endpoint, and we did not have a priori knowledge of the relative degree of improvement in OSDI for patients treated with TearCare or Restasis, it seemed (and remains so) a reasonable approach.Moreover, while the improvement in OSDI was numerically better for TearCare patients at the Month 6 endpoint, the small difference (2.35) and the large standard deviations (>17) suggest that, even if this difference was real, it would have required an impossibly large sample size to achieve statistical significance and would remain of questionable clinical significance.