Do unpublished data make a difference? The case of Tamiflu

In cooperation with TI/ Transparency International
Thursday, Dec. 6th 2012, 4:30 -  6:30 PM

Location:
Gesellschaft d. Ärzte
Frankgasse 8
1090 Wien
Bibliothek

Lecturer: 
Dr. Tom Jefferson

“Do unpublished data make a difference? The case of Tamiflu” - Hayashi’s problem: The use of regulatory information for research synthesis

In cooperation with TI/ Transparency International

Tom Jefferson is one of the editors of the Cochrane Acute Respiratory Infections (ARI) Group, and a member of six other Cochrane review groups. His main research interests are the application of systematic reviewing methods to studies of antivirals and vaccines of different designs (such as trials, economic evaluations and epidemiological studies) and editorial peer review. Tom Jefferson was a visiting research fellow at the UK Cochrane Centre in Oxford (1999-2012) and presently is the scientific lead of the Italian HTA programme on devices and diagnostics. While pursuing his research activity, Tom Jefferson has published over 200 papers and co-authored five books.

Tom Jefferson´s most recent activity is centred on the development of methods to incorporate regulatory information (data and comments) into Cochrane reviews using the example of the drug oseltamivir/Tamiflu for influenza to minimize the effects of reporting bias. The review is funded by the UK’s NIHR.

Content of presentation:

A recent survey has shown that only 10% of Cochrane reviews make serious efforts to search for and include unpublished material. The recent series of cases of exposure of sponsor bias changing our understanding (and is some cases the registration) of important interventions (second generation antipsychotics, rosiglitazione, riboxetine, vioxx, tamiflu) has shown that reliance on published material can be highly misleading. Journals (and ultimately research synthetisers and decision-makers) are usually presented with a very short summary of a selected trial which is part of a larger research programme. Given the growing realization that these form a potentially biased evidence base, we may need to develop explicit methods for including regulatory material in systematic reviews or require producers to make all material available to journals (an unrealistic option). First however we need to know this is feasible and worthwhile. Tom Jefferson will present and discuss some of these issue on the basis of the oseltamivir (Tamiflu) review, starting with the story of how his team realized their previous Cochrane review on Tamiflu were biased and how they went about addressing the issue.“Our 2006 neuraminidase inhibitors (NI) for influenza Cochrane review was misleading.
Its optimistic findings were wholly based on a mixture of published and glimpses of unpublished material taken at face value without adequate critical appraisal. Efforts to ascertain the presence or extent of publication bias were not in depth. Subsequent versions of the review have revealed the existence of considerable reporting bias. Industry has no obligation to publish all its trials, but are bound to disclose them to regulators when seeking registration. Thanks to UK NIHR funding, we are at present updating our NI review by looking only at unpublished data to minimise the risk of any type of reporting bias. Our current review includes both internal pharma trial reports which are 200-300 fold larger than their published counterparts and regulatory files. These are either currently available of requested through FOIA rules from the FDA, UK NICE, EMA and Japanese PMDA. So far regulatory material (in the guise of new drug application appraisal reports) has proved invaluable in integrating internal trials reports and providing additional information for their critical interpretation.”

Main related publications:

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

Jefferson T, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database of Systematic Reviews 2006;(3):CD001265.

Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 2009;339:b5106

Doshi P. Neuraminidase inhibitors: the story behind the Cochrane review. BMJ 2009;339:b5164

Cohen D. Complications: tracking down the data on oseltamivir. BMJ 2009;339:b5387.

Godlee F, Clarke M. Why don’t we have all the evidence on oseltamivir? BMJ 2009;339:b5351
Editor's Choice: We want raw data, now. BMJ 2009; 339 doi: 10.1136/bmj.b5405

Smith J, on behalf of Roche. Point-by-point response from Roche to BMJ questions. BMJ 2009;339:b5374.

Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965.pub3.

Doshi P, Jones MA, Jefferson T. Rethinking credible evidence synthesis. BMJ 2012;344:d7898 doi: 10.1136/bmj.d7898.

Drug Data Shouldn't Be Secret by Peter Doshi and Tom Jefferson
The New York Times, April 10, 2012. URL: http://www.nytimes.com/2012/04/11/opinion/drug-data-shouldnt-be-secret.html  Shortened URL: http://nyti.ms/Ivgh9c

Doshi P, Jefferson T, Del Mar C (2012) The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience. PLoS Med 9(4): e1001201. doi:10.1371/journal.pmed.1001201
Short URL: http://bit.ly/HIbwqO. PDF for printing: http://bit.ly/HFBYTV