Dr. Michiel LuteijnUniversity of Ulster

EUROCAT

May 22nd, 2014Jordanstown

Research Integrity

The Tamiflu story

2003

1999, 2006, 2008

“Oseltamivir at 150mg daily was effective in preventing lower respiratory tract complications in influenza cases (OR 0.32, 0.18-0.57)”.1 Based on Kaiser data.2

Introduction

Letter to Cochrane Library

Communication by Cochrane authors to Kaiser and the two lead authors of the published trials August 2009.

• Kaiser and those authors suggested to contact Roche since, after 6-9 years, they did not have data available.

• Roche confidentiality agreement October 2009.• Agreement stated Jefferson not allowed to publish data.

• Roche did send excerpts from final study reports of all 10 trials to Jefferson October 2009.

• After being turned down, and meeting the deadline, Jefferson published his systematic review in BMJ, December 2009.

• December 2009, Roche promised access to “full study reports” from the Kaiser paper “with the coming days”.

Further developments

Kaiser versus published only

Jefferson T et al. BMJ 2009;339:b5106

“Because of the moderate effectiveness of neuraminidase inhibitors, we believe they should not be used in routine control of seasonal influenza. We are unsure of the generalisability of our conclusions from seasonal to pandemic influenza. Evidence on the effects of oseltamivir in complications from lower respiratory tract infections, reported in our 2006 Cochrane review, may be unreliable. Evidence on serious harms of neuraminidase inhibitors is limited. Independent randomised trials to resolve the uncertainties surrounding effectiveness are needed.”

Systematic review update

Further uncertainty

Roche stated that the additional studies: “provided little new information and would therefore be unlikely to be accepted for publication by most reputable journals.”

Nicholson3

Treanor4

???

Study “M76001”

In the Kaiser analysis and in company documents sent to Jefferson, its abstract credits Professor Treanor as the sole author and is given the study number M76001.

BMJ asked Professor Treanor why M76001 was not published and Treanor replied that as far as he could remember, the JAMA trial was the only large study of Oseltamivir he participated in.

•Treanor further stated: “I am pretty sure that data were ultimately published by Fred Aoki” (Aoki FY, Macleod MD, Paggiaro P, et al)

The paper published by Professor Aoki did not correspond to trial M76001.

Roche stated “It’s not infrequent that you may have somebody who authors but they don’t actually present it at a conference, it depends upon their availability.”

December 7th, 2009, Roche published study summaries (including key data) on roche-trials.com.

December 2010: Roche commissioned meta-analysis published.• “An independent reanalysis of 11 randomized clinical trials shows that oseltamivir

treatment reduces the risk of lower respiratory tract complications requiring antibiotic treatment by 28% overall (95% confidence interval [CI], 11%–42%)” 5

January 2011: Cochrane Library requests data from European Medicines Agency and American FDA.

• April – May 2011: EMA sends Cochrane data on 19 trials.

October 2012: BMJ Editor reminds Roche data still not available and Cochrane Library publishes systematic review update.

April – November 2013: Roche sends data to Jefferson et al.

Further developments

End of the story? (1)

Jefferson T et al. BMJ 2014;348:bmj.g2545

Jefferson T et al. BMJ 2014;348:bmj.g2545

End of the story? (2)

Conclusions

“Given that oseltamivir is now recommended as an essential medicine for the treatment of seriously ill patients or those in higher risk groups with pandemic influenza,4 5 the issues of mode of action, lack of sizeable benefits, and toxicity are of concern. This is made worse by the record and stated intentions of governments to distribute oseltamivir to healthy people to prevent complications and interrupt transmission on the basis of a published evidence base that has been affected by reporting bias, ghost authorship, and poor methods.

We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the WHO list of essential drugs, and its use in clinical practice as an anti-influenza drug.”6

End of the story? (3)

Take home message

When interpreting papers, a critical attitude is required for manufacturer sponsored studies.

Awareness of selective reporting of results by manufacturers. Withholding trial outcomes by industry is still legal.

Roche did not break any laws, any “blame” for this situation does not solely lie with Roche, but also with the regulatory community and the scientific community.

References

1 Jefferson T, Demicheli V, Rivetti D, Jones M, Di Pietrantonj C, Rivetti A. Antivirals for influenza in healthy adults: systematic review. Lancet. 2006 Jan 28;367(9507):303-13.

2 Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med. 2003 Jul 28;163(14):1667-72.

3 Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, Rode A, Kinnersley N, Ward P. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000 May 27;355(9218):1845-50.

4 Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis R, Riff D, Singh S, Kinnersley N, Ward P, Mills RG. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000 Feb 23;283(8):1016-24.

5 Hernán MA, Lipsitch M. Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clin Infect Dis. 2011 Aug 1;53(3):277-9. doi: 10.1093/cid/cir400. Epub 2011 Jun 15.

6 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 Apr 9;348:g2545. doi: 10.1136/bmj.g2545.