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Questions remain about effectiveness of Tamiflu, experts warn

Key trial data promised by manufacturer two years ago still not forthcoming

Caroline White

Wednesday, 18 January 2012

The safety and effectiveness of flu drug Tamiflu still remain unclear because the manufacturer has failed to release key trial data for independent scrutiny, experts warn today.

Tamiflu has become the mainstay of influenza treatment in the UK. It has also made it on to the World Health Organisation’s list of Essential Medicines and Roche’s claims continue to be supported by influential health agencies.

Following an in-depth investigation by the BMJ, the drug’s manufacturer Roche promised the journal two years ago that it would release key Tamiflu trial data for independent review, but it has so far failed to deliver on that promise.

Now, a new report published today by the Cochrane Collaboration in the BMJ says this leaves critical questions unanswered about how well the drug works.

The Cochrane researchers set out to test Roche’s claim that Tamiflu prevented complications and reduced the number of people needing hospital treatment.

But their investigation was hampered by Roche’s refusal to provide all of its trial data for analysis.

The team obtained some clinical study reports from the European Medicines Agency (EMA), but found inconsistencies with published reports and possible under-reporting of side effects.

When previously questioned by the BMJ, Roche also admitted that some of the published papers had been ghostwritten.

A BMJ investigation, also published today, reveals how different regulators took different approaches to the data submitted to them, leading to conflicting messages about the drug’s effectiveness.

The EMA released a proportion of the clinical study reports relating to the Tamiflu trials to Cochrane, but it admits that it did not ask for the remainder from the manufacturer, although it was legally entitled to do so. The regulator has since told the BMJ that it plans to start publishing reports for all drugs submitted for approval in the next few years.

"We hope very much that the EMA will indeed take this important step in making the full study reports available. But we are still a long way away from having a full trial history for all drugs in clinical use. Public safety and the proper use of public money demands that we should stop at nothing less than this," comments Dr Fiona Godlee, BMJ Editor-in-Chief.

Meanwhile, the US Food and Drug Administration (FDA), which has carried out a detailed review of the Tamiflu trial programme, chose not to include the largest ever trial of Tamiflu when considering the drug for approval. It states that “Tamiflu has not been shown to prevent such complications [serious bacterial infections].”

However, the US Centers for Disease Control and Prevention (CDC) continue to cite key published trials of Tamiflu, claiming a reduced risk of influenza complications, even after Roche admitted that some of these trials have been ghostwritten.

Dr Godlee says: "The discrepancies between the conclusions reached by different regulators around the world highlights the absurd situation we find ourselves in. In a globalised world, regulators should cooperate and pool their limited resources. Otherwise we will continue to waste money and risk people's health on drugs that don't work."

The investigation also raises questions about Tamiflu’s clinical effects. After careful evaluation of trial data, the Cochrane group say that Tamiflu appears to affect antibody production – a claim that Roche refutes. This is important, says Cochrane, because influenza vaccination relies on an antibody response to be effective. But when asked by the BMJ, Roche refused to explain how the drug works.

As such, the Cochrane group says that “until more is known about the mode of action of neuraminidase inhibitors, health professionals, patients and other decision makers need to reflect on the findings of this review before making any decision about the use of the drug.”

Cochrane also argues that Tamiflu’s ability to prevent the spread of influenza has not been shown in trials. Yet this is one of the main reasons governments around the world have spent billions of dollars stockpiling Tamiflu in case of a pandemic.

Roche maintain they provided the Cochrane team with enough information to conduct their evaluation, but the Cochrane team say this is not the case.

Dr Peter Doshi from Johns Hopkins University School of Medicine says: "In the BMJ in December 2009, Roche promised full study reports to any legitimate investigators. They have not provided a single full study report to Cochrane, despite our repeated requests."

However, in a statement to OnMedica, a spokesperson for Roche said full clinical study data has been made available to health authorities around the world for their review as part of the licensing process.

“It is the role of global health authorities to review detailed information on medicines when assessing benefit/risk.

“All completed Roche sponsored clinical studies on the safety and efficacy of Tamiflu are available as peer-reviewed publications or in summary form on www.roche-trials.com. More detailed clinical trial reports are available for use by investigators on a password-protected site, enabling researchers to verify the findings of these studies and publications relating to them.

“Roche provided the Cochrane group with access to 3,200 pages of very detailed information, enabling their questions to be answered.

“Roche stands behind the robustness and integrity of our data supporting the efficacy and safety of Tamiflu.”

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