9 April 2014
Cochrane review A159 published:
Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965 DOI: 10.1002/14651858.CD008965.pub4
Authors conclude: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.
- Cochrane review questions effectiveness of neuraminidase inhibitors. [BMJ. 2014]
- Oseltamivir and zanamivir have limited effect on symptoms and do not reduce hospitalisation or serious complications of influenza. [Evid Based Med. 2014]
- Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. [Sao Paulo Med J. 2014]
- Review: Neuraminidase inhibitors reduce symptomatic influenza; oseltamivir does not reduce hospitalizations. [Ann Intern Med. 2014]
- Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. [Cochrane Database Syst Rev. 2012]
9 April 2014
Complete set of 107 full clinical study reports are made available:
The following is a guest post from Tom Jefferson, Peter Doshi and Carl Heneghan. We asked them to tell the story behind their recent Cochrane systematic review  and dataset in Dryad  which holds valuable lessons about the evidence-base on which major public health recommendations are decided.
Complete set of peer reviewers’ comments from 2009 are made available Tamiflu, Relenza, and influenza: what the data do (or don’t) tell us. 174 pages of peer review comments to the BMJ review articles made available at bmj.com.
“CDC continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct to influenza vaccination in the treatment of influenza.”
Posted at: http://www.cdc.gov/media/haveyouheard/stories/Influenza_antiviral2.html
9 April 2014
Systematic review published in BMJ with linked analysis and editorials published.
Heneghan CJ, Onakpoya I, Thompson M, Spencer EA, Jones M, Jefferson T. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348. DO10.1136/bmj.g2547. UL http://www.bmj.com/content/348/bmj.g2547
Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348. DO 10.1136/bmj.g2545. http://www.bmj.com/content/348/bmj.g2545
Linked analysis and editorials:
- Abbasi K. The missing data that cost $20bn. BMJ 2014; 348. DO 10.1136/bmj.g2695. http://www.bmj.com/content/348/bmj.g2695
- Loder E, Tovey D, Godlee F. The Tamiflu trials. BMJ 2014; 348. DO 10.1136/bmj.g2630 http://www.bmj.com/content/348/bmj.g2630
- Jefferson T, Doshi P. Multisystem failure: the story of antiinfluenza drugs. BMJ 2014;348. DOi 10.1136/bmj.g2263. http://www.bmj.com/content/348/bmj.g2263
- Krumholz HM. Neuraminidase inhibitors for influenza. BMJ 2014; 348. DO 10.1136/bmj.g2548. http://www.bmj.com/content/348/bmj.g2548
- Freemantle N, Shallcross LJ, Kyte D, Rader T, Calvert MJ. Oseltamivir: the real world data. BMJ 2014; 348. DO 10.1136/bmj.g2371.
- Jack A. Tamiflu: “a nice little earner”. BMJ 2014; 348. DO 10.1136/bmj.g2524. http://www.bmj.com/content/348/bmj.g2524
10 April 2014
Roche press release on Cochrane review findings: Cochrane Acute Respiratory Infections Group’s analysis is flawed in assessment of Tamiflu® (oseltamivir).
Ben Goldacre,the Guardian: What the Tamiflu saga tells us about drug trials and big pharma.
15 April 2014
Mark Jones criticises methods used by Muthuri et al.
Kmietowicz Z. Study claiming Tamiflu saved lives was based on “flawed” analysis. BMJ 2014;348:g2228
1 May 2014
Cochrane review included in the James Lind Library: The first Cochrane review to be based exclusively on regulatory data.
15 May 2014
Lancet editorial suggests that Cochrane review results and observational data are broadly consistent and decisions on influenza complications management should be based on observational data. “The findings of the Cochrane Collaboration and those from observational studies are not in conflict: they provide evidence on different outcomes, for different groups of patients, and across different settings. What matters is being able to reduce risk, mitigate the complications of influenza, and save lives. Neuraminidase inhibitors remain an essential part of our armamentarium to lessen the impact of influenza.”
Antivirals for influenza: where now for clinical practice and pandemic preparedness?
Lancet 2014; 384: 386–87.
16 June 2014
Responses to Muthuri et al published by Jones, M., Del Mar, C., Hama, R. Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality. Lancet Respiratory Medicine, 2014, 2(7): e9e10. And by Wolkewitz M, Schumacher M. Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality Lancet Respiratory Medicine 2014 ; 2(7): e8e9.
1 September 2014
New Zealand’s Medsafe Medicines Committee rejects Cochrane review findings. New Zealand Medicines and Medical Devices Safety Authority Medicines Adverse Reaction Committee. Oseltamivir (Tamiflu) for Influenza.
Citations alone were enough to predict favorable conclusions in reviews of neuraminidase inhibitors. Journal of Clinical Epidemiology 10/2014; “Favorable conclusions in reviews about neuraminidase inhibitors can be predicted using only information about the articles they cite. The approach highlights how evidence exclusion shapes conclusions in reviews and provides a method to evaluate citation practices in a corpus of reviews.”
30 September 2014
Risk of bias in industry-funded oseltamivir trials published conoclding “As information increased in the document, this increased our assessment of bias. This may mean that risk of bias has been insufficiently assessed in Cochrane reviews based on journal publications.”
1 October 2014
NICE states that the Cochrane review provides no new evidence. Final recommendation post consultation: The technology appraisal programme recommends that, as proposed to consultees, TA158 should remain on the ‘static list.
National Institute of Clinical Excellence. Review of TA158; The paper stated: We consider that the results of the Cochrane update are unlikely to change the recommendations of TA158 and TA168.
Reviewers with financial conflicts of interest more likely to present evidence about NIs in a favorable manner
Review concludes that “Reviewers with financial conflicts of interest may be more likely to present evidence about neuraminidase inhibitors in a favorable manner and recommend the use of these drugs than reviewers without financial conflicts of interest.” Financial conflicts of interest and conclusions about neuraminidase inhibitors for influenza: an analysis of systematic reviews 2014 Oct 7;161(7):5138. doi:10.7326/M140933.
4 October 2014
Cochrane reviewers respond to Van Tam et al’s Lancet editorial.
“Observational data are useful to answer many questions, such as whether treatments are harmful or not. However, the fact that experimental data from randomised trials are less prone to error from bias than are observational studies is not debatable.” Del Mar C, Doshi P, Hama R, Jones M, Jefferson T, Heneghan C, et al. Neuraminidase inhibitors for influenza complications. The Lancet 2014; 384: 1260-61.
Nguyen-Van-Tam JS, Openshaw PJM, Nicholson KG repsond . Neuraminidase inhibitors for influenza complications. The Lancet 2014; 384: 126-162. “We do not dismiss the findings in the Cochrane review. The finding that no signal exists suggesting that neuraminidase inhibitors reduce serious complications is not unexpected in light of the fact that the clinical trials reviewed were done in community settings, were based on mostly healthy patients with mild influenza-like illness, and were not designed or powered to assess effect on severe illness.”
16 October 2014
Roche publishes detailed 69 page response to Cochrane review.
Cochrane Review authors’ response to Roche comments (23 March 2015)
20 October 2014
England's CMO rejects review findings for non-applicability of evidence.
Public Accounts Committee Oral evidence : Tamiflu Recall, HC 677. Monday 20 October 2014
Inquiry: Tamiflu recall
Sir Andrew Dillon, Chief Executive, National Institute for Health and Care Excellence; Dr Ian Hudson, Chief Executive, Medicines and Healthcare Products Regulatory Agency; Professor Carl Heneghan, Director, Centre for Evidence-based Medicine, University of Oxford and Dr Fiona Godlee, Editor in Chief, British Medical Journal give evidence.
Public Accounts Committee report: Access to clinical trial information and the stockpiling of Tamiflu
1 November 2014
Public Health England publishes guidance on use of antivirals in influenza.
24 November 2014
BMJ Editor in Chief and Cochrane review group responses to CMO’s evidence.
Public Accounts Committee on Tamiflu. Statement from Dr Fiona Godlee, Editor in Chief, The BMJ, November 24 2014.
CMO defends decision to stockpile Tamiflu and says she would do it again. BMJ 2014;349:g6386
Fellow witness Fiona Godlee, editor in chief of The BMJ, challenged this, saying, “The observational data cannot be relied upon for evidence of benefit in the same way that clinical trials could be. “If there is a pandemic we must insist that there be a trial of Tamiflu or other more modern antivirals because not to do that would itself be unethical. The current system is insufficiently transparent and insufficiently independent for the regulation and evaluation of drugs, and that has to change.”
Carl Heneghan, Director of the Centre for Evidence-Based Medicine at the University of Oxford, also giving evidence, said, “Observational data does have uses. It is important, but many people in this room know it’s subject to such bias that you would not want to use it to establish treatment effects.”
Will Tamiflu recommendations change this winter? Andrew Jack reports on renewed pressure to remove the antiviral drug oseltamivir from the World Health Organization’s powerful list of essential medicines.
1 December 2014
Review on the harm of oseltamivir and its mechanism of toxicities (Japanese) Published in the Japanese Independent Drug bulletin “The Informed Prescriber”. Hama R.