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Oseltamivir tablet on red background © Shutterstock

In April 2014, the Cochrane review on neuraminidase inhibitors was published alongside BMJ summary reviews. The review found that while Oseltamivir and zanamivir have small, non‐specific effects on reducing the time to alleviation of influenza symptoms, oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children, and both drugs do not reduce the important outcomes such as pneumonia and hospitalisations.

Below is an account of the events, publications and media coverage that followed the publication of our 2014 review, compiled by Professor Carl Heneghan:

Neuraminidase inhibitors for preventing and treating influenza in adults and children
Cochrane Systematic Reviews https://doi.org/10.1002/14651858.CD008965.pub4. 10 April 2014
Tom Jefferson, Mark A Jones, Peter Doshi, Chris B Del Mar, Rokuro Hama, Matthew J Thompson, Elizabeth A Spencer, Igho J Onakpoya, Kamal R Mahtani, David Nunan, Jeremy Howick, Carl J Heneghan

 

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.

9 April 2014

Complete set of 107 full clinical study reports are made available: 

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children http://dx.doi.org/10.5061/dryad.77471 Tamiflu, Relenza, and influenza:

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 [1] and dataset in Dryad [2] 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 responds: 

“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:

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.

1 January 2015

JAMA republishes an article from The Medical Letter on Drugs and Therapeutics Concludes “Chemoprophylaxis with antiviral drugs is not recommended for healthy persons exposed to influenza. A neuraminidase inhibitor, either oseltamivir (Tamiflu). Antiviral Drugs for Seasonal Influenza 2014-2015. JAMA 2015; 313(4): 41314.

Roche funded IPD meta-analysis (Dobson et al) published in Lancet – covering editorial refers to as “independent” contested by neuriminidase authors:

3 February 2015

Tools for Practice evaluates the evidence on clinically relevant primary care topics The Alberta College of Family Physicians (ACFP)’s Tools for Practice summarises the evidence (www.acfp.ca/tools-for-practice) so far.

5 February 2015

Family doctor, Paul Roblin, challenges the independence of the Dobson et al meta-analysis. Paul Roblin on Dobson et al’s Lancet Tamiflu reanalysis:  blogs.bmj.com

Lenzer documents citation bias in CDC statements on the use of antivirals and Roche funding of CDC’s “Take 3” campaign. Lenzer J. Why aren’t the US Centers for Disease Control and Food and Drug Administration speaking with one voice on flu? BMJ 2015; 350: h658. In May 2015 this is followed by: Lenzer J. Centers for Disease Control and Prevention: protecting the private good?

1 March 2015

Cochrane reviewers summarise results of review. The authors subsequently published the underlying documents simultaneously with the Cochrane review, endorsing the concept of open science” Roche and Van Tam et al also publish articles in the same issue. Mark Jones, Tom Jefferson, Peter Doshi, Chris Del Mar, Carl Heneghan, Igho Onakpoya. Commentary on Cochrane review of Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Clinical Microbiology and Infection 2015, 21, 217–221.

Roche respond: Clinch, B., Smith, J. Roche perspectives on Tamiflu. 
Clinical Microbiology and Infection 2015, 21, 226–229

J.S. Nguyen-Van-Tam, S. Venkatesan, S.G. Muthuri, P.R. Myles. Neuraminidase inhibitors: who, when, where? 
Clinical Microbiology and Infection 2015, 21, 222-225

3 March 2015

CDC continues recommending use of antivirals. View the latest guidance

Australian Broadcasting Corporation (ABC) Catalyst documentary on Tamiflu. "Imagine a Hollywood doomsday scenario: a flu pandemic sweeps the world, hundreds of millions of people are infected. How prepared are we for a flu pandemic? Will our stockpiles of Tamiflu stop a pandemic in its tracks? Dr Maryanne Demasi investigates.” ABC Catalyst program.

19 March 2015

Imbalance of baseline renal function between oseltamivir and placebo group reported. Participants in five prophylaxis randomized controlled trials 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 (P = 0.005). Hama R, Jones M and Jefferson T. Concerns about the randomization in the prophylaxis trials of oseltamivir. Rapid response to Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.  BMJ 2014;348:g2545

16 June 2015

England's Chief Medical Officer calls for review after statins and Tamiflu storm, reports the Guardian:  “Coming on top of the debate about Tamiflu and the response to the ONS [Office for National Statistics] study on medication levels, there seems to be a view that doctors over-medicate, so it is difficult to trust them, and that clinical scientists are all beset by conflicts of interest from industry funding – and are therefore untrustworthy too. It cannot be in the interests of patients and the public’s health for this debate to continue as it is,” said the Chief Medical Officer, Sally Davies.

England’s Chief Medical Officer asks for review of drug evaluation in wake of statins controversy, reports the BMJ and the BBC.

1 September 2015

Letter responses to Dobson et al published in Lancet. A series of responses to Dobson et al  meta-analyses of individual patient published in the Lancet including concerns over the methods. Oseltamivir for influenza. Lancet 2015; 386: 113336.(9999):11345. Doi: 10.1016/S01406736(15)002020. Oseltamivir for influenza. Peter Doshi, Carl Heneghan, Tom Jefferson.; Oseltamivir for influenza. Mark Jones, Rokuro Hama, Chris Del Mar.; Oseltamivir for influenza.Arnold S Monto, Joanna Dobson, Stuart Pocock, Richard J Whitley.

2 September 2015

The Conversation publishes a piece on the Tamiflu story. This draws several comments. Cochrane reviewer Jefferson points out McVernon’s attempts at blurring the Dobson authors’ conflicts of interest as well as her own. McVernon does not respond, despite two further reminders.

8 October 2015

Academy of Medical Sciences and Wellcome Trust publish report exploring the scientific evidence around the treatment of influenza, including the use of existing antivirals, research priorities, methodological improvements and the pipeline of new treatments . The report laments the uncertainty over the evidence base of NIs and the failure to carry out research during the 2009 influenza pandemic. 
Use of neuraminidase inhibitors in influenza, Academy of Medical Sciences and Wellcome Trust, October 2015.

Guardian: Experts call for tests on use of flu drugs in pandemic

28 October 2015

Doshi P, Jefferson T post  Concerns about this article and a further response Neuraminidase Inhibitors and Influenza Infection. JAMA Intern Med. 2016

October 2015

JAMA publishes viewpoint on using observational studies.
Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence? JAMA Intern Med. 2015 Oct 19;1.

February 2016

ECDC launches consultation ECDC preliminary scientific advice - Expert Opinion on Neuraminidase Inhibitors for prevention and treatment of influenza. Download the draft scientific advice.

Independent drug bulletin Prescrire summarises story: “Over a 15-year period, Roche, the company that markets Tamiflu, has hampered independent analysis of the assessment data on oseltamivir in the treatment of influenza." 

Full text available for free download.

March 2016

Hama R, Jefferson T, Heneghan C. Cochrane reviewers’ comments on the ECDC draft preliminary Scientific Advice paper.

UK Cochrane Centre publishes a timeline of media coverage.

JAMA editors publish an editorial on data sharing: "For instance, previous reports involving rofecoxib and oseltamivir illustrate the problem of incomplete or misleading reporting of clinical trial."

Peter Doshi and colleagues challenge the evidence base used by the CDC to make recommendations on the use of Oseltamivir. Tamiflu For All? Evidence Of Morbidity In CDC’s Antiviral Guidelines.

May 2016

Rokuro Hama publishes a review of the evidence of the mechanism of action of neuraminidase inhibitors in Infectious Diseases.

The independent drug Bulletin “Med Check The Informed Prescriber” (Japanese) introduces the Cochrane team’s critical comments on the ECDC experts’ draft advice on neuraminidase inhibitor use.

June 2016

Cochrane author team publish HTA review and find no effect of oseltamivir on mortality in patients with 2009A/H1N1 influenza.

Rokuro Hama reviews the evidence of harms on neuraminidase inhibitors in the Journal of Infectious Diseases. In a linked commentary Tom Jefferson explains the significance.

August 2016

Mark Jones publishes on Immortal time bias in observational studies of time-to-event outcomes, and strongly suggest time-dependent exposures be included as time-dependent variables in hazard-based analyses.

September 2016

Neuraminidase Inhibitors and Hospital Mortality in British Patients with H1N1 Influenza A published: A Re-Analysis of Observational Data.

January 2017

Financial competing interests were associated with favourable conclusions and greater author productivity in nonsystematic reviews of neuraminidase inhibitors. J.Clin.Epidemiol. 2016 Dec;80:43-49.

February  2017

Masking survival biases in observational treatment studies of influenza patients – Wolkewitz, Schumacher published.

March 2017

WHO Expert committee recommends transfer of Tamiflu from the Core to the Complementary Essential Medicines List.

April 2017

Early administration of neuraminidase inhibitors in adults hospitalized for influenza does not benefit survival: a retrospective cohort study published in the European Journal of Clinical Microbiology and Infectious Diseases.

16 June 2017

Academy of Medical Sciences publishes report: Action needed to prevent confusion over medicines in relation to tamiflu and statins evidence. Enhancing the use of scientific evidence - full report Download.

July 2017

WHO downgrades the status of oseltamivir. Mark H Ebell,  BMJ 2017; 358.

WHO’s new list focuses on antibiotic resistance, adds expensive drugs, and downgrades Tamiflu. Michael McCarthy BMJ 2017;358.

August 2017

European Centre for Disease Prevention and Control: Expert panel reviews neuraminidase inhibitors for the prevention and treatment of influenza.

An ECDC expert opinion concludes that there is clear evidence supporting the use of neuraminidase inhibitors in the treatment and prevention of influenza. Moreover, the current recommendations in European countries on the use of the neuraminidase inhibitors oseltamivir and zanamivir are appropriate and should be applied by prescribing physicians. Expert opinion on neuraminidase inhibitors for the prevention and treatment of influenza - [PDF-1.15 MB].

12 February 2018

HealthNewsReview.org: Stories about tragic flu deaths wrongly portray Tamiflu as a panacea
But in fact, the FDA has concluded that Tamiflu is not proven to saves lives, as medical journalist Jeanne Lenzer wrote in 2015 in the BMJ.

12 May 2018

Daily Mail: GPs are told to give patients Tamiflu pills amid worsening flu outbreak
Professor Carl Heneghan of Oxford University, who published a major study four years ago suggesting Tamiflu is ineffective, said: However, Professor Carl Heneghan of Oxford University, who published a major study four years ago suggesting Tamiflu is ineffective, said: ‘The chief medical officer seems not to be able to understand evidence-based medicine.

May 2019

BMJ updates its Tamiflu campaign page

The BMJ’s first open data campaign aimed to pressure companies into releasing the underlying clinical trial data for two globally stockpiled anti-influenza drugs, Tamiflu and Relenza. The campaign lasted nearly four years and was ultimately successful, and helped galvanize a movement towards increased transparency of clinical trial data.