Wednesday, 17 September 2014

Oseltamivir (Tamiflu) for Influenza... A Crushing Cochrane Review

Billions of dollars has been spent around the world stockpiling neuraminidase inhibitors to be used in case of pandemic influenza. The presumption is that they are effective, have little side effects, prevent transmission, complications and will save the planet. Was this money well spent?

The 2014 Cochrane review to describe the benefits and harms of oseltamivir was truly a gargantuan and unprecedented undertaking. The authors recognized there was the substantial risk of reporting bias as all of the RCT’s investigating oseltamivir were industry sponsored. Would a drug company that stands to make billions of dollars suppress or hide information that may be damning to their cause? I’ll let you decide.

In order to get around reporting bias, the authors conducted a four year campaign to obtain full clinical study reports of the oseltamivir trial programs. This has never been done before. Full study reports are not simply the papers that get published or rejected from peer review journals. No, they are the raw data and a lot more. In the case of oseltamivir, clinical study reports were of a mean length of approximately 1300 pages each.  In the end, the authors succeeded in accessing the reports and relevant regulatory comments totalling approximately 150,000 pages! How anyone could go through all of this information is beyond me. Heck, I struggled to read their 18 page Cochrane review in the BMJ.

To get right to the point, let’s look at the conclusions.

How well does oseltamivir work? It reduces the time to first alleviation of symptoms by about 16 hours. This represents a reduction in time from having the flu for a full 7 days to about 6.3 days in the treatment group.  This of course likely represents best case scenario as all of the study designs were industry supported.  

Does it reduce admissions to hospital? No.

Could conclusions be drawn on the ability of oseltamivir to interrupt viral transmission? No and nor could the FDA. This leads one to question why this drug has been stockpiled.

What about potential harms of oseltamivir? It increased the risk of nausea (NNTH 28), and vomiting (NNTH 22). In addition it increases the risk of headaches and renal & psychiatric syndromes. One interesting fact to come out of all of this was the “placebo” used in the trials contained dehydrocholic acid and dibasic calcium phosphate dehydrate. Both can cause GI symptoms which may have been a source of bias in favour of minimizing the potential harms of oseltamivir.

The conclusions as stated by the authors strike me as very cautious and measured. It made me wonder if they were concerned about the legal power of a wealthy pharmaceutical company. The last sentence of their abstract simply states, “The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.” It took them 4 years of struggle, expending so much time, effort, and energy to come up with this wimpy conclusion? My guess is the authors would have a different opinion over a glass of beer.

At least the authors did leave a little sting at the end of their manuscript buried on page 9 of 18. They conclude by stating:

Given that oseltamivir is now recommended as an essential medicine for the treatment of seriously ill patients or those in higher risk groups with pandemic influenza, the issues of mode of action, lack of sizeable benefits, and toxicity are of concern. This is made worse by the record and stated intentions of governments to distribute oseltamivir to healthy people to prevent complications and interrupt transmission on the basis of a published evidence base that has been affected by reporting bias, ghost authorship, and poor methods.

We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the WHO list of essential drugs, and its use in clinical practice as an anti-influenza drug.




Covering:

Jefferson T, Jones M, Doshi P, et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545


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