A joint investigation by the BMJ and Channel 4 News (UK) reports that an updated expert review reveals there is no clear evidence that the antiviral drug most commonly used against influenza -oseltamivir (Tamiflu) – prevents complications like pneumonia in healthy people.

The claims about the effectiveness of oseltamivir against complications have been an important reason for Governments worldwide to decide to stock up on these drugs as part of global pandemic preparedness plans. In doing so, Governments have been reported to spend great amounts.

The expert review published on BMJ.com today has led to a cooperative investigation by Channel 4 News and the BMJ into oseltamivir. A feature article is published on bmj.com and a film detailing the investigation will be broadcast on Channel 4 News (UK).

The study updates a 2006 review published in The Cochrane Library. It acknowledges that oseltamivir and other neuraminidase inhibitors have a modest effect in reducing flu symptoms. Also, it decreases infectivity in otherwise healthy adults by about one day. In addition, the researchers remark that there is insufficient published data in order to confirm if oseltamivir reduces complications in otherwise healthy adults.

According to Dr Fiona Godlee, Editor in Chief of the BMJ, this updated review leaves essential questions about effectiveness unanswered. She says: “Governments around the world have spent billions of pounds on a drug that the scientific community now finds itself unable to judge.”

Roche, which produces oseltamivir, has estimated sales of £1.6billion (CHF 2.7bn) this year alone from the drug.

Since the spread of the influenza A/H1N1 (swine flu) pandemic began in April 2009, the use of neuraminidase inhibitors, especially oseltamivir, has increased radically. Neuraminidase inhibitors were seen as the answer to the pandemic in the absence of an effective vaccine and because of resistance to previous drugs used against flu.

The team of researchers is led by Professor Chris Del Mar from Bond University in Australia. They analyzed twenty published trials that focused on prevention, treatment and adverse reactions.

But their investigation was hindered by the “paucity of good data” available from authors and the company that produces oseltamivir (Roche). Consequently the team discarded eight key trials which were never fully published that were included in the earlier review because they were unable to independently verify the results. As a result, they conclude that they have no confidence in claims that oseltamivir reduces the risk of complications of influenza in otherwise healthy adults. They believe it should not be used in routine control of seasonal influenza.

The failure to access the data means that previous evidence on the effects of oseltamivir on flu complications may be unreliable. They advise governments to set up various studies to monitor the safety of neuraminidase inhibitors.

Professor Nick Freemantle and Dr Melanie Calvert from the University of Birmingham evaluated observational studies based on a list provided to the Cochrane authors by Roche. They say in closing that “oseltamivir may reduce the risk of pneumonia in otherwise healthy people who contract flu. However, the absolute benefit is small, and side effects and safety should also be considered.”

They consider the data as poor and remark: “Interpretation of the studies was difficult … It seems likely that some patients were included in more than one study, which undermines the ability of these studies to provide independent estimates.”

Professor Freemantle says he sees “very little evidence to support the widespread use of oseltamivir in the otherwise healthy population who are developing signs of influenza like illness.” He adds: “We have remarkably few resources in this country to spend on pharmaceuticals on health and it’s surprising to see such widespread use of oseltamivir. But I suppose that once you’ve gone and bought lots of doses then it’s a bit like the situation with gun control in the US. If you have a gun in the house it’s much easier to use it. But it does not mean it’s the right thing to do.”

Dr Fiona Godlee and Professor Mike Clarke, Director of the UK Cochrane Centre, note that this updated review is essential because it calls into question “not only the effectiveness of oseltamivir but the whole system by which drugs are evaluated, regulated and promoted.”

In an editorial in the BMJ, they call for new global legislation to guarantee that “once a trial is completed, there needs to be ready access to the raw data behind any analyses used to licence and market a drug.”

“When vast quantities of public money, and large amounts of public trust, are placed in drugs, the full data must be accessible for scrutiny by the scientific community,” they conclude. “Pending full disclosure and independent review of the raw data from Roche, the risks and benefits of oseltamivir remain uncertain.”

A BMJ feature article and a film to be shown on Channel 4 News tonight details the investigation undertaken jointly by the BMJ and Channel 4 News. It shows a complex interaction between politics, public health planning, poor trial data, publishing and drug regulation. It raises questions about the use of ghostwriters in some of the manuscripts, as alleged by former employees of the medical communication company hired by Roche. It calls to the attention why one of the largest trials of oseltamivir was not published.

In a response Roche declared that they “firmly believe in the robustness of the data”. They point out that full access to data has been granted to Governments and regulatory authorities.

As a result of this investigation, Roche has committed to make all study summaries of oseltamivir – including key data – available on a password-protected site. But until then, the Cochrane authors say that “any claims regarding a reduction in risk of serious complications from influenza in healthy adults still cannot be verified.”

“Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and metaanalysis”
Tom Jefferson, researcher, Mark Jones, statistician, Peter Doshi, doctoral student, Chris Del Mar, dean; coordinating editor of Cochrane Acute Respiratory Infections Group
BMJ 2009; 339:b5106
doi:10.1136/bmj.b5106

“What can we learn from observational studies of oseltamivir to treat influenza in healthy adults?”
Nick Freemantle, professor of clinical epidemiology and biostatistics, Mel Calvert, senior lecturer
BMJ 2009; 339:b5248

“Neuraminidase inhibitors – the story behind the Cochrane review”
Peter Doshi
BMJ 2009; 339:b5164

“Why don’t we have all the evidence on oseltamivir?”
Fiona Godlee, editor in chief, Mike Clarke, director
BMJ 2009; 339:b5351

“Point-by-point response from Roche to BMJ questions”
James Smith,international medical leader, Tamiflu on behalf of Roche
BMJ 2009; 339:b5374

“Complications: tracking down the data on oseltamivir”
Deborah Cohen, BMJ
BMJ 2009; 339:b5248

“Roche replies to the authors of the Cochrane Review on oseltamivir”
James Smith, international medical leader, Tamiflu
BMJ 2009; 339:b5364

“We want raw data, now”
Fiona Godlee, editor, BMJ
BMJ 2009; 339:b5405

Channel4 Uk/news
The Cochrane Library
bmj.com

Written by Stephanie Brunner (B.A.)