This is an Accepted Manuscript of an article published by Taylor & Francis Group in Infectious Diseases on 27 Jun 2016, available online: http://www.tandfonline.com/doi/abs/10.1080/23744235.2016.1189593
In this issue of Infectious Diseases, my colleague and fellow Cochrane author Rokuro Hama reviews the evidence of harms on neuraminidase inhibitors (NI) with special focus on the two earliest registered molecules (Zanamivir, Relenza, Glaxo SmithKline and Oseltamivir, Tamiflu Roche).
Most readers will be familiar with parts or the whole of story of the search for the evidence of the effects (benefits and harms) of NIs. The story centres on efforts to update and verify the data included in the relevant Cochrane review first published in 2000 (1). In 2009 circumstances led the Cochrane reviewers (I am one of them) to question the reliability of the published evidence base and identify the existence of large numbers of unpublished clinical trials (up to 60% of the treatment indication trials have never been published) (2). In turn this led to a protracted exchange of requests with the manufacturers who initially stonewalled our requests but had to concede after all the relevant correspondence was published (bmj.com/tamiflu). The story became a catalyst for renewed calls for transparency in clinical trials management and data access (3-5).
The result was the release of over 150 thousand pages of Oseltamivir and Zanamivir trials and other studies (107 in total) and animal study reports and the publication of the most comprehensive independent review on the topic ever published. This huge quantity of information was made publicly available alongside the publication of the Cochrane review (6, 7).
The data on benefits showed a verifiable modest effect compared to placebo: a few hours’ shortening of symptoms, principally fever. None of the other statements on the properties of NIs could be verified (effects on influenza complications, interruption of viral transmission, effects on death). Not happy with this situation, industry funded 2 case series with historical or concurrent controls which reaffirmed the beneficial narrative (8, 9). In addition Roche through an intermediary also funded an individual participant data meta-analysis which was branded as “independent” by an editorial in its prestigious host journal, despite industry funding and the presence in the authors’ list of a member of the Gilead Science board (10, 11). Gilead Science are holders of the patents for oseltamivir.
The conclusions of these studies are improbable, as trial evidence does not confirm the observational evidence and the Dobson et al individual level meta-analysis was carried out without a protocol and disregarding the flimsiness of the outcomes used in the trials. For example “pneumonia” was a clinical diagnosis without instrumental confirmation of any kind. The exaggeration of benefits and understatement of harms of Nis is known to be linked to funding source (12).
So, if benefits are questionable the spotlight moves to harms, the other side of the vital user equation for pharmaceuticials.
Rokuro Hama in the linked paper provides what is probably the most extensive review of the evidence of harms ever undertaken. Hama’s evidence comes from a powerful mix of mostly hitherto untapped sources, including regulatory papers, clinical study reports, animal studies and published evidence. The evidence fails to support a mechanism of action mediated through antiviral action put forward by the manufacturers.
This seems to be independent of any effects on influenza viruses as shown in our Cochrane review in which symptoms relief occurs in a whole population with influenza-like symptoms many of whom will not have influenza. The evidence points to a central action on pre-inflammatory and inflammatory pathways, with consequent amelioration of symptoms but toxic effects of immunity, cardiac, metabolic and renal functions and neurological pathways. At best the situation is one of uncertainty which has never been fully explained as the data has remained under lock and key for a decade while the world was told that Nis were drugs capable of delaying a pandemic and affecting influenza complications (the two reasons for stockpiling Nis). Despite what we now know, stockpiling is alive and well and such claims are still being made at the highest level. In 2015 CDC Director Dr Thomas Frieden stated that “Antiviral flu medicines are underutilized. If you get them early, they could keep you out of the hospital and might even save your life.” (13)
Dr Tom Jefferson
Honorary Research Fellow
Centre for Evidence Based Medicine
Oxford OX2 6GG
TJ was a co-recipient with RH of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for preventing and treating influenza. In addition TJ receives royalties from his books published by Il Pensiero Scientifico Editore, Rome and Blackwells. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in a litigation case related to the antiviral oseltamivir, in two litigitation cases on potential vaccine-related damage and in a labour case on influenza vaccines in healthcare workers in Canada. TJ has acted as a consultant for Roche (1997-99), GSK (2001-2), Sanofi-Synthelabo (2003), and IMS Health (2013) and in 2014 was retained as a scientific adviser to a legal team acting on oseltamivir. In 2014-16 TJ was a member of three advisory boards for Boerhinger Ingelheim and is holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ is a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine.
- Jefferson T, Demicheli V, Deeks J, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2000;(2):CD001265.
- Doshi P. Neuraminidase inhibitors–the story behind the Cochrane review. BMJ. 2009 Dec 8;339:b5164. doi: 10.1136/bmj.b5164.
- Loder E, Tovey D, Godlee F. The Tamiflu trials. BMJ 2014; 348. DO 10.1136/bmj.g2630 UL http://www.bmj.com/content/348/bmj.g2630.
- Jefferson T, Doshi P. Multisystem failure: the story of anti-influenza drugs. BMJ 2014;348. DOi 10.1136/bmj.g2263. UL http://www.bmj.com/content/348/bmj.g2263
- Krumholz HM. Neuraminidase inhibitors for influenza. BMJ 2014; 348. DO 10.1136/bmj.g2548. UL http://www.bmj.com/content/348/bmj.g2548
- Tamiflu, Relenza, and influenza: what the data do (or don’t) tell us? Dryad Data 2014 https://blog.datadryad.org/2014/04/17/tamiflu-data/
- Muthuri SG, Venkatesan S, Myles PR, et al, for the PRIDE Consortium Investigators. Eﬀectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with inﬂuenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014; 2: 395–404.
- Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Lim WS et al. Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an IPD meta-analysis. Influenza Other Respir Viruses. 2015 Nov 25. doi: 10.1111/irv.12363. [Epub ahead of print].
- 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.
- Kelly H, Cowling BJ. Inﬂuenza: the rational use of oseltamivir. Lancet 2015; 385: 1700–02.
- 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):513-8. doi: 10.7326/M14-0933.
- Transcript for CDC Telebriefing: Update on Flu Season 2014-15. http://www.cdc.gov/media/releases/2015/t0108-fluupdate.html