“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

Prof Chris Del Mar
There’s a problem here – data being collected, patients take part in a trial and that data never published. And that’s a disgrace. That can’t be allowed to continue.
Prof Peter Collignon
The reality is more data’s become available. It doesn’t appear to be working anywhere near as well as my expectation was, and I think a lot of people’s expectation.
Dr Fiona Godlee
I think it’s very hard to explain why this behaviour by the pharmaceutical industry in suppressing data over many years is not considered as misconduct. As many people would say, in a scientific experiment, if you suppress data, that’s considered misconduct. We should be pushing back and saying this is unacceptable, this is not justified by commercial interests. This is about patients’ health, public health and we absolutely have to have all the trial data of trials that are performed on the members of the public.

“Since 1999 a large and growing body of observational data, including in hospitalized patients, shows there are benefits to using antiviral drugs beyond the treatment of uncomplicated illness. In medical practice, these drugs have been documented to reduce serious flu complications”. This connects with an earlier statement by CDC Director Dr Thomas Frieden “Antiviral flu medicines are underutilized. If you get them early, they could keep you out of the hospital and might even save your life.”

Why CDC Recommends Influenza Antiviral Drugs

The 2014-2015 flu season has been a difficult one for a number of reasons, including circulation of H3N2 viruses which are typically associated with more severe flu seasons, and reduced vaccine effectiveness because circulating H3N2 viruses are different or have “drifted” from the H3N2 virus used to make vaccine. A number of media and online outlets have inquired about the public health rationale behind CDC’s influenza antiviral recommendations. This statement provides background information and explains the rationale for CDC’s influenza antiviral recommendations.

Getting a flu vaccine is the best way to prevent influenza illness and protect against its potentially deadly consequences. When a person is sick with flu, however, antiviral flu drugs are a treatment option. They work best when taken within 48 hours of becoming sick.

Transcript for CDC Telebriefing: Update on Flu Season 2014-15

Cochrane review not cited: statements are made on the basis of industry funded studies which are referenced in the first document.

Paul Roblin on Dobson et al’s Lancet Tamiflu reanalysis: an independent review group. Really?

Repsosted from www.cebm.net and blogs.bmj.com

On 30.1.15 the Lancet published a re-analysis of Oseltamavir effects in symptomatic influenza like illness “Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials”.  This trial was authored by Joanna Dobson, Richard J Whitley, Stuart Pocock, Arnold S Monto.

The lancet supplemented this re-analysis with an article by Heath Kelly and Benjamin Cowling entitled “Influenza: the rational use of oseltamivir”

The Kelly and Cowling article claims that the re-analysis was done by an independent research group. I am concerned that not all relevant links of the authors of the Dobson Lancet paper have been sufficiently declared.  The competing interests are very vaguely presented, omitting key facts

The Dobson paper contains the following: 

Page 9 of the paper has the text below
Contributors
JD did the statistical analyses and prepared data tables and figures. All authors contributed to writing of the manuscript and made substantial contributions to conception and design of the study, and analysis and interpretation of data.
Declaration of interests
ASM reports fees from Biocryst and Roche outside of the submitted work. RJW reports fees as a board member of Gilead Sciences, funding for travel from Roche to attend an Influenza Resistance Committee meeting, and fees as Associate Editor of the Journal of Infectious Diseases. JD and SP declare no competing interests.
Acknowledgments
This study was funded by the Multiparty Group for Advice on Science (MUGAS) Foundation through an unrestricted grant from Roche Pharmaceuticals. Neither party had a role in analysis, interpretation, reporting or the decision to submit for publication. We thank Roche for providing the data and answering data specific queries.

Page 4 of the paper has the text below
Role of the funding source
The meta-analysis was funded by the Multiparty Group for Advice on Science (MUGAS) who assembled a multidisciplinary team to examine the overall data from trials of oseltamivir in adults. The team agreed an individual patient data analysis was the most robust approach, and to cover the costs the MUGAS Board applied for an unrestricted grant from Roche. This unrestricted grant stipulates that Roche would not be involved in the actual review process in any way other than providing the requested data dictionaries and datasets. The results were not shared with Roche until the analysis was completed. The London School of Hygiene & Tropical Medicine received a grant from MUGAS to partly fund Joanna Dobson’s salary while she worked on this project. No other monies were received by any of the authors.

I have looked into the biographies of the authors and found the following

1. Prof Richard J Whitley is a paediatrician interested in viruses and works with/for CDC
   His declaration given above seems inadequate.
   The relevance of the reference to Gilead is that Gilead Science holds the patent for Tamiflu and this should be explicitly stated
   Should something like this not be declared in the Lancet paper?
   Gilead directors are listed HERE
   Whitley joined Gilead’s Board of Directors in 2008.
2. Prof Arnold Monto
   He reports fees from Biocryst and Roche outside of the submitted work but also received about 41,000 US $ he got from GSK in 2009-13.
   See list HERE
   GSK produces Relenza the other antiviral product advocated for flu
3. Ms Joanna Dobson
   Her publications can be found  HERE
   There are 10 since 2010 but not a single one on influenza, not a single first authored and not a single systematic review
   This raises the question of what qualifies Dr Dobson to be the lead author on such a paper
4. Prof Stuart Pocock
   He has expertise in statistical methods and clinical trials and describes his clinical area as being CV disease.
   Statisticians can only deal with the information given to them by others

There are further issues about the trial being funded by MUGAS
Comment about MUGAS  (see block of text below)

In 2013, Roche announced that in the interests of transparency it would supply any data requested by what it described as a “third party group”, the Multiparty Group for Advice in Science (MUGAS).
In fact, while the name might lead you to imagine an independent body bringing together representatives of a number of organisations to consider a range of issues (rather like All-Party Groups in the UK Parliament), MUGAS is funded by Roche and is led by four scientists, three of whom are advisers to Roche. It appears to have been set up specifically as part of the attempt to counter the Cochrane’s criticisms.
Another organisation involved is European Scientists Working on Influenza (ESWI).  On their websites, MUGAS and ESWI give as their point of contact the same mobile telephone number in Belgium [13, 14]. The name MUGAS is a registered trademark of Semiotics, a company that describes its mission as “translating science to the world,” but whose actual activity seems mostly to be concerned with influenza and in particular oseltamivir [15].

Details of Semiotics
Both MUGAS and ESWI are brands of Semiotics
See also  Semiotics Mind Map

We need to know a lot more about how Semiotics, MUGAS and ESWI are funded and who influences what they say and do.

The second article of the series reports a statement by CDC Director Thomas Frieden declining to comment on the CDC’s statement that “CDC does not accept commercial support”

43. 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:

44. Lenzer J. Centers for Disease Control and Prevention: protecting the private good?

“The re-analysis was funded by an unrestricted grant from Roche but was done by an independent research group, thus seeking to overcome the suggested bias associated with industry-funded studies” Kelly et al editorial.

Dobson et al. Acknowledgments

This study was funded by the Multiparty Group for Advice on Science (MUGAS) Foundation through an unrestricted grant from Roche Pharmaceuticals. Neither party had a role in analysis, interpretation, reporting or the decision to submit for publication. We thank Roche for providing the data and answering data specific queries.

Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet 2015; 385: 1729–37.

Interpretation

Our findings show that oseltamivir in adults with influenza accelerates time to clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admittance to hospital, but increases the occurrence of nausea and vomiting.

Linked editorial:

Heath Kelly, Benjamin J Cowling Influenza: the rational use of oseltamivir The Lancet, Volume 385, Issue 9979, 2–8 May 2015, Pages 1700-1702 PDF (177 K)

Referred to by

• Mark Jones, Rokuro Hama, Chris Del Mar Oseltamivir for influenza
• The Lancet, Volume 386, Issue 9999, 19–25 September 2015, Pages 1133-1134  PDF (88 K) Supplementary content
• Ryan P Radecki Oseltamivir for influenzaThe Lancet, Volume 386, Issue 9999, 19–25 September 2015, Page 1134 PDF (42 K) Peter Doshi, Carl Heneghan, Tom Jefferson Oseltamivir for influenzaThe Lancet, Volume 386, Issue 9999, 19–25 September 2015, Pages 1134-1135  PDF (145 K) Supplementary content
• Kenji Kubo, Satoko Otsu, Nobuhiro Komiya Oseltamivir for influenza The Lancet, Volume 386, Issue 9999, 19–25 September 2015, Page 113 PDF (135 K)

• Arnold S Monto, Joanna Dobson, Stuart Pocock, Richard J Whitley  Oseltamivir for influenza – Authors’ reply The Lancet, Volume 386, Issue 9999, 19–25 September 2015, Pages 1135-1136  PDF (145 K)
• Heath Kelly, Benjamin J Cowling Influenza: the rational use of oseltamivir The Lancet, Volume 385, Issue 9979, 2–8 May 2015, Pages 1700-1702 PDF (177 K)

Concludes “Chemoprophylaxis with antiviral drugs is not recommended for healthy persons exposed to influenza. A neuraminidase inhibitor, either oseltamivir (Tamiflu) or zanamivir (Relenza), remains the drug of choice for treatment of patients with influenza. Oseltamivir is preferred for use in pregnant women and in patients with underlying airway disease.” Evidence from the the Cochrane review is not cited.

From The Medical Letter on Drugs and Therapeutics. Antiviral Drugs for Seasonal Influenza 2014-2015. JAMA 2015; 313(4): 41314.

Published in the Japanese Independent Drug bulletin “The Informed Prescriber”.

Hama R. Harm of oseltamivir and the mechanisms of toxicities – latest information. The Informed Prescriber 2014; 29(12): 94100. (in Japanese)：

The recommendations are based on observational data and conclude that “it is essential that physicians treating severely unwell patients in any setting are not deterred from prescribing NAI drugs as a result of confusion over efficacy. This is especially true for patients hospitalised with proven or suspected influenza”.

The use of antivirals for the treatment and prophylaxis of influenza: PHE position statement. Department ofHealth 2014.

Key messages

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.”

Godlee said, “The only evidence available that was publically used to support the decision [to stockpile oseltamivir] was the Kaiser systematic review, 3 which was funded by Roche, of 10 trials, of which only two had been published. That was the basis for the decision to stockpile the drug as I understand it.”

Davies said that other work done had played a part in the government’s decision to buy the drug at the time.

Will Tamiflu recommendations change this winter? BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g6742 (Published 27 November 2014) Cite this as: BMJ 2014;349:g6742

The World Health Organization is at the centre of a fresh debate on whether it should remove an antiviral drug from its influential list of recommended medicines, following a growing number of studies scrutinising the medicine’s value in treating influenza.

Members of the Cochrane collaboration have called for oseltamivir (Tamiflu) to be taken off WHO’s essential medicines list, a document of more than 300 drugs considered necessary to meet basic healthcare standards. It was first added in 2009, the year the H1N1 pandemic flu strain was identified.

Chris Del Mar, professor of public health at Bond University in Australia and one of the Cochrane authors, said: “Oseltamivir was included at a time when it looked as though it was effective and it seemed prudent to planners to stockpile.”

His comments come after the publication of an update to the Cochrane review of clinical trials of oseltamivir and another neuraminidase inhibitor, zanamivir. Their work followed more than four years of efforts by the researchers and The BMJ to obtain raw trial data from drug companies and to track down submissions to regulators made around the world (www.bmj.com/tamiflu). The Cochrane authors concluded, on the basis of a meta-analysis of 46 trials covering 24 000 patients, including data not previously made public, that the drugs shortened symptoms in seasonal influenza cases by less than a day and did not reduce the number of hospital admissions. (Read More)

Public Accounts Committee Oral evidence: Tamiflu Recall, HC 677. Monday 20 October 2014

Public Accounts Committee Oral evidence : Tamiflu Recall, HC 677. Monday 20 October 2014

Inquiry: Tamiflu recall

5.00pm: Una O’Brien, Permanent Secretary, Department of Health Professor Dame Sally Davies, Chief Medical Office,
Department of Health

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

Dr Fiona Godlee, EditorinChief, British Medical Journal

33. Public Accounts Committee report: Access to clinical trial information and the stockpiling of Tamiflu

34. 20 Oct 2014 Tamiflu Recall oral evidence | PDF version ( 200 KB) HC 677 | Published 21 Oct 2014

35. 20 Oct 2014 Tamiflu Recall oral evidence | PDF version ( 200 KB) HC 677 | Published 28 Oct 2014

“We do not dismiss the findings in the Cochrane review.² The finding that no signal exists suggesting that neuraminidase inhibitors reduce serious complications² 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”

Nguyen-Van-Tam JS, Openshaw PJM, Nicholson KG. Neuraminidase inhibitors for influenza complications. The Lancet 2014; 384: 126-162.

We would like to thank Chris Del Mar and colleagues for their interest in our Comment.¹ They assert that their Cochrane review² was based on full clinical study reports of all manufacturer-sponsored randomised trials. In fact, only a subset (46 of the 107 Clinical Study Reports obtained) were formally analysed. The study undertaken by Muthuri and colleagues³ was funded by Roche, but its design, conduct, interpretation, and report preparation were done independently of the funder. Exhaustive attempts were made to obtain datasets suitable for analysis from around the world. Compared with the 80 datasets received, few (n=15) were not shared because of review board or governmental restrictions (n=3), or inability to meet project timelines (n=12).³ None of the contributors of data declared industry funding for acquisition or assembly of their dataset. (Read More)

“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.

In their Comment (Aug 2, p 386), Jonathan Nguyen-Van-Tam and colleagues suggest that findings from our Cochrane review² and a study of observational data³ are consistent. In our review, which was based on full clinical study reports of all manufacturer-sponsored randomised trials, we did not find evidence that neuraminidase inhibitors improve important outcomes of influenza, whereas the Roche-funded individual analysis of a subset of retrospective case reports suggested that neuraminidase inhibitors do have some beneficial effect. These observational studies were of patients admitted to hospital for influenza, some of whom apparently benefited from neuraminidase inhibitors.³ Most treated patients received oseltamivir, with a minority receiving zanamivir. Similar evidence was cited in a statement from Roche.⁴ Our Cochrane review did not include similar patients, but was based on typical patients with influenza-like illness.

However, the hypothesis that oseltamivir protects against complications of influenza proposed by Nguyen-Van-Tam and colleagues, together with the observational studies that they cite in support of their hypothesis,³ can be dismissed by our finding that neuraminidase inhibitors did not seem to reduce severe complications of influenza, and oseltamivir specifically did not seem to reduce risk of admission to hospital (admission to hospital was not reported for zanamivir), but seemed to suppress production of antibody to the virus and cause potentially serious side effects.² Furthermore, oseltamivir reduced time to alleviation of symptoms the least for trials of patients with co-morbidities such as asthma and chronic obstructive airways disease.²

The appeal to observational data in support of oseltamivir is curious because the original notion that oseltamivir was effective for treatment of influenza complications came from a meta-analysis⁵ of a subset of randomised trials—both published and unpublished—which was in contrast to the US Food and Drug Administration’s requirement that the drug label made no claims for effectiveness for influenza complications. ⁶ This absence of effectiveness is supported by our Cochrane review (based on a full set of clinical study reports), which found no protective benefit of oseltamivir. Now drug manufacturers and Nguyen-Van-Tam and colleagues are claiming that randomised trial data are no longer adequate. Yet, when the results of reviews of randomised trials agreed with their views, Nguyen-Van-Tam and colleagues accepted the reviews. Now that the Cochrane review does not support their hypothesis, they appeal to contradictory real-world (observational) data.³ This inconsistency needs to be addressed.

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. The randomised trial data should therefore be trusted—insufficient evidence exists to justify conclusions about oseltamivir’s effectiveness for treatment of influenza. Nguyen-Van-Tam and colleagues seem to suggest that pandemic planners should act to minimise public outcry rather than accept the best available evidence. This advice could risk scarce health-care resources stockpiling a probably ineffective drug.

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.”

Dunn AG , Arachi D , Hudgins J , Tsafnat G , Coiera E , Bourgeois FT . Ann Intern Med. 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.

The response states: “the Cochrane authors have made basic errors in their assessment of oseltamivir efficacy data, overinterpreted the limited safety data they evaluated, and wholly ignored certain types of data”.

Roche feedback on “Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children”.

National Institute of Clinical Excellence. Review of TA158; Oseltamivir, amantadine and zanamivir for the prophylaxis of influenza, and TA168; Amantadine, oseltamivir and zanamivir for the treatment of influenza)

The paper stated: We consider that the results of the Cochrane update are unlikely to change the recommendations of TA158 and TA168.

• First, the population for whom oseltamivir and zanamivir are recommended by NICE is the ‘at-risk’ group as defined in TA158 and 168. The Cochrane update reports on evidence for healthy adults and children, without providing results for subgroups, including what could be considered as the ‘at-risk’ population.
• Second, although the effect sizes in terms of symptomatic benefits are perhaps a little lower than was assumed in the analyses performed for NICE in TA168, they are not inconsistent with the range of estimates applied in different scenarios explored for that guidance. In those scenarios more conservative symptomatic benefits (which appear comparable to those reported here) were applied, resulting in oseltamivir as still being cost-effective.
• Furthermore, the Committee noted that in all of the population subgroups, treatment with either antiviral drug was associated with reductions in the average duration of symptoms compared with placebo, although the difference was not statistically significant in all subgroups. The Committee acknowledged that the reduction in duration of symptoms was generally greater for the ‘at risk’ population compared with healthy populations. Page 3 of 16
• Third, although it is more difficult to compare inputs for complications given the different definitions employed in the Cochrane paper and the approach used in the economic model for TA168 (i.e. linking all complications via treatment effect on antibiotic use), the results presented in the Cochrane re view don’t appear to be particularly different to the inputs used for TA168, and hence it is considered unlikely that this would significantly alter the conclusions.
• Furthermore, excluding complications only made a difference when combined with changes to other assumptions (e.g. QoL) in themodel used for TA168. In these combined scenarios, the ICER increased to >£30k in the ‘otherwise healthy’ population (see Tables 7.30 and 7.31 page 193 of the Assessment Group report). Importantly, these scenarios remained below £30k in the at-risk populations. These scenarios were discussed in full by the committee and their position (i.e.complications less plausible for otherwise healthy adults) is stated in paragraphs 4.3.13-4.3.16 of the FAD.
• Finally, the Cochrane review reports an increase in adverse events of a neuropsychiatric nature in the trials for oseltamivir in adults.
• The Cochrane review reports that: ‘in prophylaxis trials of oseltamivi there was a significant increase in patients with psychiatric adverse events over the on and off treatment periods (RR 1.80, 95%CI 1.05 to 3.08, I2 statistic = 0%; RD 1.06%, 95%CI 0.07 to 2.76; NNTH = 94, 95% CI 36 to 1538)’. Such a result was not reported for the treatment trials of oseltamivir or for any of the trials with zanamivir. Although this is important new data, and potentially could be relevant to be considered in a technology appraisal, we consider it first and foremost something for the regulators to look at.
• Second, it is unclear what the signal for these adverse events is in the group of interest in TA158 ‘at risk patients’ as the Cochrane review only reports of ‘healthy adults’ in this respect.
• Third, even if this signal is exactly replicated in the at risk group, with the same intensity, and the same distribution over the various psychiatric conditions, it is difficult to be certain about the impact on the cost effectiveness of the drugs without performing the analyses. The signal is low for oseltamivir (2.20%), representing 44 events in 2000 subjects, compared with a comparably low signal for placebo (1.32%-19 events in 1434 subjects), leading to a small difference; 0.88% in favour of placebo. Finally, it is not
• clear what level of severity of depression-the main event in this category–was reported for patients in these trials, although it is reported by Cochrane that of the 66 events in this category, 12 were classified as ‘severe intensity’ (10 oseltamivir, 2 placebo)..Again, three respondents agreed with the proposal to move the guidance to the static list. Two respondents provided ‘no comment’, and the Cochrane Acute Respiratory Infections Group disagreed. On balance, NICE has come to the view that the guidance does not, at this stage, need reviewing