BMJ Demands Raw Data From Pharma Clinical Trials

The controversy surrounding the frenzied promotion of the drug, Tamiflu (oseltamivir) has exploded in several scientific venues and even in the US and UK media. The controversy may be even more instructive about the systemic issues that undermine  the integrity of the drug and vaccine review and analysis process than the Vioxx catastrophe.

This week’s BMJ contains six articles detailing the essential issues involved in the Tamiflu controversy: included are independent critics’ analyses as well as company counterclaims, and two editorials (excerpts below) that critique the current system which not only fails to detect serious adverse effects, the system allows manufacturers to control the trials and conceal the safety data. Physicians and the public are misled with a false sense of security about the safety and effectiveness of patented drugs and vaccines.
The deception is orchestrated by company marketing masquerading as evidence which prominent industry-paid academic physicians promote as "science-based" information.

For example, a much cited favorable analysis by Kaiser et al (2005) was funded by the drug’s manufacturer Roche. The analysis was based entirely on 10 trials funded by Roche: of which only two had been published in peer reviewed journals. All 10 trials were authored by Roche employees and paid academic consultants

The system has provided companies an opportunity to make spectacular profits from the widespread use of defective drugs and vaccines that have caused irreversible harm.

"The current system isn’t working. Worse than that, it gives a false sense of security. The system’s failures have left a legacy of drug evaluations for which, in the absence of better information, we must assume the same levels of confusion and uncertainty as for oseltamivir. The drug industry directly or indirectly undertakes the majority of all drug evaluations, so most of the evidence used to support drug policy and treatment remains shrouded in secrecy. In only a minority of cases will the data have been subject to full independent analysis and interpretation. In many if not most cases, the only people who have seen the entire dataset are company employees."
See: Editorial, Why don’t we have all the evidence on oseltamivir?

Indeed, we learn how independent Cochrane Collaboration reviewers were hoodwinked into trusting a company funded meta-analysis of unpublished data–data that was undisclosed to the Cochrane reviewers:

"The previous reviewers endorsed the conclusion that oseltamivir reduces complications such as pneumonia and bronchitis by implicitly trusting that the unpublished data were verifiable. This trust now seems naive. The fact that a trust in unpublished data extends to many systematic reviews of neuraminidase inhibitors by other researchers and was not questioned until… a paediatrician from Japan, Keiji Hayashi, submitted a comment to the Cochrane Collaboration that would ultimately leave us doubtful about the ability of systematic reviews to deal with the challenges of contemporary pharmaceutical evaluation…"

"The previous Cochrane review placed its trust in publications and included Kaiser’s unpublished data, but to do so once again, despite our inability to obtain data sufficient to perform an independent analysis, would have shifted our position from that of trust in publication to that of trust in secrecy." The revised review dropped Kaiser’s paper from its analysis.

Notwithstanding the positive spin provided by the Kaiser analysis, which concluded that Tamiflu reduces complications, Roche, apparently did not itself make any such claims about complications. A Tamiflu.com webpage reads, "Treatment with TAMIFLU has not been proven to have a positive impact on these outcomes," referring to pneumonia, other respiratory diseases, and influenza related death.

However, a footnote on that website undermines the company’s pretense of candor: "THIS [WEB]SITE IS INTENDED FOR U.S. AUDIENCES ONLY."
On its global website, Roche.com, it asserts that "Tamiflu delivers … [a] 67 percent reduction in secondary complications such as bronchitis, pneumonia and sinusitis in otherwise healthy individuals." 

BMJ editor, Fiona Godlee, challenges Roche to disclose the drug’s complete clinical trial data so that independent scientists can evaluate the actual risk / benefit of the vaccine–on the basis of scientific data, not the hearsay of the manufacturer and its financially compromised scientists.

Her challenge is really directed at the pharmaceutical industry, not just Roche. It gets to the heart of the systemic corruption of science, clinical practice, government healthcare policies that have encouraged system wide fraud.

"We don’t know yet whether this episode will turn out to be a decisive battle or merely a skirmish in the fight for greater transparency in drug evaluation. But it is a legitimate scientific concern that data used to support important health policy strategies are held only by a commercial organisation and have not been subject to full external scrutiny and review. It can’t be right that the public should have to rely on detective work by academics and journalists to patch together the evidence for such a widely prescribed drug. Individual patient data from all trials of drugs should be readily available for scientific scrutiny."

Contact: Vera Hassner Sharav

10 December 2009
BMJ 2009;339:b5405
Editor’s Choice
We want raw data, now
Fiona Godlee, editor, BMJ

fgodlee@bmj.com

This week’s BMJ is dominated by a cluster of articles on oseltamivir (Tamiflu) (doi:10.1136/bmj.b5351, doi:10.1136/bmj.b5387, doi:10.1136/bmj.b5106, doi:10.1136/bmj.b5164, doi:10.1136/bmj.b5248, doi:10.1136/bmj.b5364). Between them the articles conclude that the evidence that oseltamivir reduces complications in otherwise healthy people with pandemic influenza is now uncertain and that we need a radical change in the rules on access to trial data.

Briefly, in updating their Cochrane review, published this week (doi:10.1136/bmj.b5106), Tom Jefferson and colleagues failed to verify claims, based on an analysis of 10 drug company trials, that oseltamivir reduced the risk of complications in healthy adults with influenza. These claims have formed a key part of decisions to stockpile the drug and make it widely available.

Only after questions were put by the BMJ and Channel 4 News has the manufacturer Roche committed to making "full study reports" available on a password protected site. Some questions remain about who did what in the Roche trials, how patients were recruited, and why some neuropsychiatric adverse events were not reported. A response from Roche is published in our letters pages (doi:10.1136/bmj.b5364) and their full point by point response is published online (doi:10.1136/bmj.b5374).

Should the BMJ be publishing the Cochrane review given that a more complete analysis of the evidence may be possible in the next few months? Yes, because Cochrane reviews are by their nature interim rather than definitive. They exist in the present tense, always to be superseded by the next update. They are based on the best information available to the reviewers at the time they complete their review. The Cochrane reviewers have told the BMJ that they will update their review to incorporate eight unpublished Roche trials when they are provided with individual patient data.

Where does this leave oseltamivir, on which governments around the world have spent billions of pounds? The papers in this week’s journal relate only to its use in healthy adults with influenza. But they say nothing about its use in patients judged to be at high risk of complications—pregnant women, children under 5, and those with underlying medical conditions; and uncertainty over its role in reducing complications in healthy adults still leaves it as a useful drug for reducing the duration of symptoms. However, as Peter Doshi points out (doi:10.1136/bmj.b5164), on this outcome it has yet to be compared in head to head trials with non-steroidal inflammatory drugs or paracetamol. And given the drug’s known side effects, the risk-benefit profile shifts considerably if we are talking only in terms of symptom relief.

We don’t know yet whether this episode will turn out to be a decisive battle or merely a skirmish in the fight for greater transparency in drug evaluation. But it is a legitimate scientific concern that data used to support important health policy strategies are held only by a commercial organisation and have not been subject to full external scrutiny and review. It can’t be right that the public should have to rely on detective work by academics and journalists to patch together the evidence for such a widely prescribed drug. Individual patient data from all trials of drugs should be readily available for scientific scrutiny.

Cite this as: BMJ 2009;339:b5405
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BMJ
Editorials
Why don’t we have all the evidence on oseltamivir?
Fiona Godlee, editor in chief1, Mike Clarke, director2

The full data from drug trials must be available for scrutiny by the scientific community

This week the BMJ publishes an updated Cochrane review on neuraminidase inhibitors in adults with influenza.1 The review and a linked investigation undertaken jointly by the BMJ and Channel 4 News2 cast doubt not only on the effectiveness and safety of oseltamivir (Tamiflu) but on the system by which drugs are evaluated, regulated, and promoted.

In the process of updating their review, Jefferson et al found several important inconsistencies. Prompted by a reader of their previous update,3 they attempted to reconstruct the evidence from a much cited analysis on which they had based their previous conclusions. The analysis, by Kaiser et al,4 looked specifically at the effects of oseltamivir on the risk of hospital admission and complications (pneumonia and other lower respiratory tract infections) in people with influenza. Jefferson et al noted that the Kaiser analysis was funded by the drug’s manufacturer Roche and was based entirely on 10 trials funded by Roche, only two of which had been published as articles in peer reviewed journals. All 10 included trials were authored by Roche employees and paid academic consultants. The Cochrane reviewers could find no independently funded trials of oseltamivir in healthy adults.

Other questions also arose, as outlined by one of the Cochrane reviewers Peter Doshi5 and by Deborah Cohen in our feature.2 Which authors of the trials had seen the raw data? Why were key authors of the published papers and abstracts not named in company documents submitted for drug approval, while people named in these documents were not included in the published papers? Were ghost writers involved in some of the manuscripts, as alleged by former employees of the medical communication company hired by Roche? Why were the rates of influenza infection in the trials so high? And why were serious adverse events under-reported?
………..

This case exposes how much of the evidence on drug safety and effectiveness is taken on trust. Governments and international bodies have relied heavily on the Kaiser et al analysis and on observational studies to justify the stockpiling and widespread use of oseltamivir.2 7 10 No doubt they assumed that others had looked critically and comprehensively at the complete dataset. Those others might include drug regulators and health technology assessors such as NICE, as well as journal editors and Cochrane reviewers. But that isn’t how the system works……..