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Rapid response to:


Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

BMJ 2014; 348 doi: (Published 09 April 2014) Cite this as: BMJ 2014;348:g2545

Rapid Response:

Concerns about the randomization in the prophylaxis trials of oseltamivir

In our Cochrane review [1], we reported a non-significant increase in renal events in oseltamivir prophylaxis trials on-treatment (RR 3.17, 95% CI 0.96 to 10.49) by random effect model. However there was a statistically significant increase (P=0.02) in sensitivity analysis using Peto’s method. We also noticed two patients in oseltamivir groups who experienced renal failure prior to death [1]: one in trial WV15825 and on in trial WV15708. While assessing the evidence in individual patient data in prophylaxis trials, we found imbalance of baseline renal disorders between the oseltamivir and placebo groups. We independently extracted the data on baseline creatinine level and concomitant renal and urinary tract diseases (renal/UTD) for five studies in total: two in adults (WV15673/WV15697), two in the elderly (WV15708; WV15825) and one in households (WV15799) [2].

Participants with high baseline creatinine level (154μmol/L or more) were significantly less reported in the oseltamivir group than in the placebo group: pooled odds ratio was 0.29 (95% CI = 0.12 to 0.69, P = 0.005, I2= 0%: Figure). In trial WV15708 which was never published, participants with high baseline creatinine level (154μmol/L or more) were significantly less reported (OR 0.23; 95%CI: 0.06, 0.82、P = 0.0168). Participants with concomitant renal/UTD were less reported (OR 0.38; 95%CI: 0.14, 0.93, p=0.0269). In trial WV15708, Proportions of participants with high baseline creatinine level and/or concomitant renal/UTD were 5.8% (11/190) and 16.5% (30/182) for oseltamivir group and placebo group respectively: odds ratio 0.31 (95%CI = 0.14 to 0.67, P = 0.0014).

In an experiment using beagle dogs to test the effects on cardiac functions such as especially QT time [3], mean baseline QTc intervals (msec±SE) were 417±16 in the control (vehicle) group (n=4) and 374±2 in the oseltamivir carboxylate (OC) group (n=4). Difference was significant (p=0.0372) by the summary data t-test. There was also evidence that the variation was higher in the control group (P=0.005; Bartlett’s test).
We don’t know the reason why such large and systemic imbalances occurred, but they are unlikely to have occurred by chance.

1. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965.pub4
2. The Dryad Digital Repository.
3. Marketing Authorization Application, Table of Contents – Volume 81 1007- Brewster M. Ro 64-0802/002 (GS-4071) cardiovascular and respiratory evaluation in the anaesthetized dog following intravenous administrations (DHB08601). RR W-142974. 1999 (disclosed document from EMA)

Competing interests: All authors were co-recipients of a UK National Institute for Health Research grant (HTA–10/80/01, Update and amalgamation of two Cochrane reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children— RH wrote two books on the harm of Tamiflu and/or antipyretics and provided scientific opinions and expert testimony on 14 adverse reaction cases related to oseltamivir in the law suits. MJ has no additional conflict of interest to be declared. TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in a litigation case related to oseltamivir and in a labour case on influenza vaccines in healthcare workers in Canada. TJ was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on oseltamivir. In the next 12 months, TJ anticipates reimbursement for travel and accommodation in a potential lawsuit related to oseltamivir, and expert witness fees for cases involving alleged harm from vaccination. TJ is a recipient of a travel grant from the Cochrane Collaboration to attend the bi-annnual editors’ meeting in 2015.

19 March 2015
Rokuro Hama
Mark Jones and Tom Jefferson
NPO Japan Institute of Pharmacovigilance
#702 Ueshio 5-1-20, Tennouji-ku, Osaka, Japan 543-0002