Reply to Cochrane Neuraminidase Inhibitors Review Team

TO THE EDITOR—Del Mar and colleagues [1] critique our meta-analysis of randomized trials of oseltamivir and lower respiratory tract complications (LRTCs) requiring antibiotic treatment in adults [2]. Del Mar et al [1] correctly note that the outcome in our meta-analysis may be misclassified because the trials did not use a standardized definition. Nondifferential misclassification would attenuate our effect estimates: the true beneficial effect of oseltamivir would be greater than that reported in our article. Del Mar et al [1] questioned whether meta-analyses should be conducted when the outcomes may be misclassified. We understand this to be a rhetorical question because they recently published a meta-analysis of these outcomes and concluded that there was no effect [3]. On a related point, we cannot attribute a motive to the US Food and Drug Administration’s statements (which are not fully consistent with the European Medicines Agency’s); we just present the available evidence. Del Mar et al [1] questioned our choice of primary outcome. The trials in our meta-analysis studied various outcomes. We chose antibiotic-treated LRTCs because they are clinically relevant, present in sufficient numbers for a meaningful evaluation, and serious enough to prevent frequent misclassification. Del Mar et al [1] suggest an outcome definition including sinusitis and otitis media, and perhaps also milder LRTCs not requiring antibiotic treatment, a suggestion at odds with their concern about outcome misclassification. Contrary to several protocols and to the approach of Kaiser et al [4], we included antibiotic-treated LRTCs even if they occurred within the first 2 days of treatment. This inclusion allowed us to perform a true intent-to-treat analysis and attenuated the estimated effect of oseltamivir compared with that previously reported [4]. Del Mar et al [1] identified 3 trials that were not included in our meta-analysis. Two of these (WP15979 and WP16137) were pediatric pharmacokinetic studies. Roche provided us with study reports for these 2 trials, and we verified that they contained no data relevant to our meta-analysis. The third trial, conducted in China [5], did not exclude patients on antibiotics at baseline and included sinusitis, tonsillitis, and otitis media in the outcome. Because Roche has no access to the trial data, we could not incorporate them in our meta-analysis. The list of Roche trials that forms the supplementary Appendix to our article [2] excluded some trials with no data relevant to our analysis. To provide a complete picture of all trials with Roche involvement, regardless of their eligibility for our meta-analysis, we requested from Roche their full list of oseltamivir trials. The list provided by Roche is included as a supplementary Appendix to this letter. An inspection of this list revealed 2 additional Chinese trials [6, 7] that were not included in our meta-analysis. One trial [6] considered only influenza-infected individuals; the other [7] was not blinded, not placebo-controlled, and reported apparently inconsistent counts. Neither trial used an outcome definition comparable to ours. Again, Roche has no access to the data from these 2 trials (correspondence on file). Because we could not perform an analysis of the 3 Chinese trials analogous to that of the trials in our meta-analysis, we performed a sensitivity analysis that ignores the differences in outcome definition and patient eligibility between the Chinese trials and the trials in our meta-analysis. Had we included these 3 trials in our meta-analysis, the pooled risk ratio would have been 0.70 (95% confidence interval, .56–.88), a slightly stronger beneficial effect than the one reported in our article. Finally, we performed extensive checks of the data sent by Roche. The analysis by Kaiser was precisely duplicated when their criteria were used. We had specifically asked Del Mar’s collaborators for checks and analyses that they considered important. We obtained no response after both in-person (meeting with Peter Doshi on 7 February 2011) and e-mail (personal correspondence, Doshi et al, 29 June 2011) requests. In summary, we agree with Del Mar et al [1] that clinical trial data should be publicly available. However, without a legal requirement, we can only rely on the manufacturers’ willingness to do so. That a manufacturer may hide or distort evidence is possible (and there are some well-known precedents), but questioning an entire research program publicly and responsibly requires evidence beyond the detection of a few inconsistencies. With the caveats described in our article, the available data indicate that oseltamivir reduced the risk of LRTCs requiring antibiotic treatment.