Review Challenges Tamiflu Efficacy

Jan. 17, 2012— -- A new review of the influenza drug oseltamivir (Tamiflu) has raised questions about both the efficacy of the medication and the commitment of its maker to supply enough data for claims about the drug to be evaluated by independent experts.

It also raises questions about the entire process of systematic review.

Researchers led by Dr. Tom Jefferson of the Cochrane Collaboration pored over 15 published studies and nearly 30,000 pages of "clinical study reports."

But, they reported, the clinical study information -- data previously shared only with regulators -- was only a part of what internal evidence suggested was available.

And many published studies had to be excluded because of missing or contradictory data, Jefferson and colleagues reported.

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The drug's maker, Switzerland-based Roche, had promised after a previous Cochrane review to make all of its data available for "legitimate analyses." After a request for the data, Jefferson and colleagues reported, the company sent them 3,195 pages covering 10 treatment trials of the drug.

But, three of the reviewers noted in a parallel report in BMJ, the tables of contents suggested that the data were incomplete.

"What we're seeing is largely Chapter One and Chapter Two of reports that usually have four or five chapters," according to the BMJ article's lead author, Peter Doshi of Johns Hopkins University.

Roche did not immediately respond to a telephoned request for comment.

The researchers then asked the European Medicines Agency (EMA) for the data, under a Freedom of Information request, and obtained a further 25,453 pages, covering 19 trials.

But that data, too, was incomplete, they said, although the agency said it was all that was available.

The FDA is thought to have the complete reports, but has not yet responded to requests for them, the researchers reported.

Regulatory agencies such as the EMA and FDA routinely see the large clinical study reports, Jefferson and colleagues said in BMJ, but systematic reviewers and the general medical public do not.

"While regulators and systematic reviewers may assess the same clinical trials, the data they look at differs substantially," they said.

The Cochrane group has been trying for several years to put together a clear-cut systematic review of the evidence on antivirals aimed at flu.

In 2006, the group concluded that the evidence showed that oseltamivir reduced the complications of the flu. But that conclusion was challenged on the basis that a key piece of data was flawed.

An updated review in 2009 -- throwing out the flawed study -- concluded there wasn't enough evidence to show that the drug had any effect on complications.

For this analysis, the Cochrane reviewers had originally intended to perform a systematic review on both of the approved neuraminidase inhibitors -- oseltamivir and zanamivir (Relenza), using the clinical study reports to supplement published trials.

In the end, they decided that for oseltamivir, they needed more detail in order to perform the review in its entirety. But, they reported, some conclusions could be drawn from published data on the 15 trials and from 16,000 pages of clinical study reports that were available before their deadline.

They also decided to postpone analysis of zanamivir (for which they had 10 trials) because the drug's maker, GlaxoSmithKline, offered individual patient data which they wanted time to analyze.