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Research

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

BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2545 (Published 09 April 2014) Cite this as: BMJ 2014;348:g2545
  1. Tom Jefferson, reviewer1,
  2. Mark Jones, senior research fellow (biostatistics)2,
  3. Peter Doshi, assistant professor3,
  4. Elizabeth A Spencer, nutritional epidemiologist4,
  5. Igho Onakpoya, research fellow in evidence-based practice and pharmacovigilance4,
  6. Carl J Heneghan, professor4
  1. 1Cochrane Acute Respiratory Infections Group, Via Puglie 23, 00187 Rome, Italy
  2. 2School of Population Health, University of Queensland, Brisbane, Australia
  3. 3Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
  4. 4Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
  1. Correspondence to: T Jefferson jefferson.tom{at}gmail.com
  • Accepted 3 April 2014

Abstract

Objective To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments (“regulatory information”).

Design Systematic review of regulatory information.

Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.

Eligibility criteria for selecting studies Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza.

Main outcome measures Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population.

Results From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval −0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for “pneumonia,” and no clinical study reports reported laboratory or diagnostic confirmation of “pneumonia.” The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined “on-treatment” and “off-treatment” periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two “pivotal” treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, −0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116).

Conclusions In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.

Footnotes

  • Research, doi:10.1136/bmj.g2547
  • We thank Matthew Thompson, Rokuro Hama, Chris Del Mar, Liz Dooley, Ruth Davis, Peter Collignon and Toby Lasserson. The National Institute for Health Research (NIHR) for Primary Care Research provides financial support for Carl Heneghan and funding for an investigators’ meeting in Oxford, UK.

  • This paper is based on Cochrane Review A159 which should be published simultaneously in the Cochrane Database of Systematic Reviews (see web extra for peer review history of reviews on neuraminidase inhibitors relevant to this review).

  • Contributors: TJ, PD, and MJ were authors of the separate relevant Cochrane review in healthy adults. TJ, PD, MJ, and CJH contributed to the writing of the protocol for this review and devised the approach strategies to the data sources. TJ reviewed regulatory material. TJ, PD, and MJ applied inclusion criteria. All authors extracted data and appraised bias. CJH, IO, and EAS checked the data. MJ carried out the statistical analyses. IO and TJ prepared the final text and all authors contributed to the final draft. CJH is guarantor.

  • Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in the Health Technology Assessment journal series (more details are available at www.nets.nihr.ac.uk/projects/hta/108001). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health. The study sponsor had no role in study design; the collection, analysis, and interpretation of data; the writing of the article; and the decision to submit the article for publication. All the authors have no ties to the manufacturer or the sponsor (apart from those disclosed) and had access to all parts of the deidentified clinical study reports from the oseltamivir trial programme.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare that all review authors have applied for and received competitive research grants. TJ, PD, MJ, and CJH are co-recipients of the NIHR grant to carry out this review. TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome and is occasionally interviewed by market research companies for anonymous interviews about phase 1 or 2 pharmaceutical products. In 2011-13 TJ acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in healthcare workers in Canada. In 1997-99 TJ acted as consultant for Roche, in 2001-02 for GSK, and in 2003 for Sanofi-Synthelabo for pleconaril (an antirhinoviral that did not get approval from FDA). TJ is a consultant for IMS Health. PD received €1500 (£1241; $2052) from the European Respiratory Society in support of his travel to the society’s September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. PD is an associate editor of the BMJ. TJ, MJ, CJH, and PD are 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 www.nets.nihr.ac.uk/projects/hta/108001). CJH receives payment for running educational courses at the University of Oxford and University of Oxford ISIS consulting services for external teaching and training. He also receives royalties for books (Evidence Based Toolkit series by Blackwell BMJ Books). MJ, IO, and EAS have no additional interests to disclose.

  • Ethical approval: Ethical approval and patient consent forms are not provided as they are not necessary for a Cochrane review.

  • Data sharing: All clinical study reports will shortly be available through the Dryad repository (www.datadryad.org).

  • Transparency: The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the synthesis of the clinical study reports in the review; that no important aspects of the included clinical study reports have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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