A four-year battle to gain full data on Tamiflu highlights concerns over the extent to which companies should share clinical trial findings and how drug regulators make decisions

Decisions by governments to stockpile the oral anti-influenza drug Tamiflu (oseltamivir) to guard against a possible pandemic and its continued use in clinical practice have been challenged by researchers after they gained access to clinical trial data previously only seen by regulators.

A four-year battle to access clinical trial data for Tamiflu suggests that the European drug regulatory system is “broken”, commentators argue

Their systematic review concludes that the antiviral provides small benefits on symptom relief, but there was little evidence that it reduces hospital admission or the risk of developing pneumonia.

Published by the Cochrane Collaboration and as two separate research articles in the BMJ, the review looks at the safety and efficacy of two antivirals based on full internal reports of 20 oseltamivir and 26 zanamivir trials; the latter neuraminidase inhibitor is the less-used inhalable antiviral Relenza.

It comes after a four-year battle to gain access to full clinical trial data from the manufacturer of Tamiflu, Roche, and highlights the ongoing debate over the extent to which the drug industry should share trial data and how drug regulatory decisions align with those of independent researchers.

“[The Cochrane researchers’] fight for the data has also shown us … how deeply flawed is the entire ecosystem of drug evaluation and regulation,” says an editorial in the BMJ, a founder member of Alltrials, an advocacy group that wants to see all clinical trials registered and results reported. “Access to data relating to drugs in current use will be largely at the discretion of the drug manufacturer or via individual requests to regulators… . [The researchers] have shown with greater clarity than ever that the current system is broken,” the editorial adds.

The researchers found that oseltamivir cut symptoms by 16.7 hours (from 7 days to 6.3 days) compared with the control group (95 per cent confidence interval 8.4 to 25.1 hours; P<0.001). In contrast, the product literature states that Tamiflu reduces the duration of illness from an average 5.2 days to 4.2 days.

The researchers also found no difference in rates of admission to hospital between the treatment groups (risk ratio 0.92, CI 0.57 to 1.50), in contrast to claims originally presented to government agencies to support stockpiling.

“We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the [World Health Organization] list of essential drugs, and its use in clinical practice as an anti-influenza drug,” clinical epidemiologist Tom Jefferson, a reviewer at the Cochrane Acute Respiratory Infections Group, and colleagues, conclude.

Researchers also found that zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, but found no evidence that it reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death.

Tamiflu: £424m spent in the UK

Since its launch in 1999, Tamiflu has made more than £11bn in sales for Roche, with half of the total spend by governments and companies around the world on stockpiles for pandemic preparations, according to a feature accompanying the BMJ editorial. The UK, for instance, paid £424m for about 40 million doses.

Both the BMJ and Cochrane have issued a call to governments and decision makers across the world, asking, in light of the review, “would you make the same recommendations today, choosing to stockpile Tamiflu?”. The authors of the review add: “We urge people not to trust in published trials alone or on comment from conflicted health decision makers, but to view the information for themselves.”

Roche: the review is flawed

The Cochrane Acute Respiratory Infections (ARI) Group identified 83 eligible Tamiflu trials (81 were sponsored by Roche) and whittled them down to 20 for its systematic review.

However, Roche has criticised the review as “flawed”, saying that it is standing by the “quality and integrity” of its data. A spokesman for Roche told PJ Online that he questioned why the review group, although it had access to 77 “completed” trials, decided to only use 20 in its analysis.

He also pointed out that the reviewers themselves have admitted that they had limited experience in analysing clinical trial documents. The reviewers say: “The main limitation of our study is our relative inexperience in dealing with large quantities of information and our lack of familiarity with certain trial documents.”

The company said that it “fundamentally disagrees” with the overall conclusions of the review. “We do not consider the ARI Group, who have identified themselves as inexperienced in dealing with such data, to be the final authority on the value of neuraminidase inhibitors.”

Daniel Thurley, Roche UK’s medical director, added: “Roche stands behind the wealth of data for Tamiflu and the decisions of public health agencies worldwide, including the US and European Centres for Disease Control & Prevention and the World Health Organization.”

A spokesman for GSK, manufacturer of Relenza, told PJ Online that it was committed to giving the Cochrane team access to the data they required from the outset and was pleased to have been able to support their research. He added that GSK continues to believe that the data from Relenza’s clinical trial programme support its effectiveness against flu and that, when used appropriately, it can reduce duration of flu symptoms by around 1–1.5 days.

European agency position and transparency moves

The European Medicines Agency said the Cochrane review does not contain any new data on Tamiflu and the results of the analysis are consistent with EU product information. It said the benefits of Tamiflu, in its approved indication, continue to outweigh its risks.

The “minor differences” arise from the fact that the Cochrane review looked only at clinical trial data whereas the agency also evaluated non-clinical and clinical pharmacology studies and extensive post-marketing safety surveillance data, it said.

Tamiflu is approved for the prevention and treatment of influenza in adults and children, it pointed out, adding that although the product information contains references to study results in which patients had fewer respiratory tract complications compared with placebo the approved indication does not cover the prevention of complications due to influenza. It added that the approved product information “does not mention any positive effect of Tamiflu on the risk of hospitalisation due to influenza”.

The EMA already announced this week that it will hold a final round of consultations on its draft policy on proactive publication of and access to clinical trial data at the beginning of May, before presenting it to its management board in June 2014.

The discussions will focus on the principles around redactions from clinical study reports. “If applied, the redactions will be based on the criteria identified by the agency for those parts of clinical trial data that exceptionally contain commercially confidential information. They will also aim to clarify how the concerned data-owners (eg, marketing authorisation holders) will be consulted before publication of their clinical study reports, and user-friendly technical measures to make the data accessible under the new policy including their terms of use,” the EMA said.

The consultation runs alongside other moves in the EU to increase transparency of clinical trials, particularly the new Clinical Trials Regulation which received a favourable vote in the European Parliament on 2 April 2014. This proposed legislation is expected to come into force in 2016.