By Michael D. Shaw
Tamiflu (Oseltamivir phosphate) is an antiviral indicated for the treatment of influenza. The drug was approved by the US FDA in 1999; and was approved by the European Medicines Agency in 2002. As of 2014, the drug had generated sales in excess of $18 billion. Based on various flu scares, the US stockpiled 65 million treatments at a cost of $1.3 billion. Other nations followed suit, so that by 2009, 96 countries possessed enough Osteltamivir for 350 million people.
In 2010, the drug was added to the World Health Organization’s Model List of Essential Medicines, on its so-called “core” list. As WHO puts it: “The core list presents a list of minimum medicine needs for a basic healthcare system, listing the most efficacious, safe, and cost-effective medicines for priority conditions.”
One can only assume that this relative fast-tracking of a drug to the WHO list—not to mention its fanatical acceptance by public health authorities—must have been based on an avalanche of clinical data. But, as would be revealed in a series of articles published in the BMJ, this “avalanche” consisted of exactly three published clinical trials. It turns out that there were many more unpublished trials, and these did not paint such a rosy picture.
As a result, Oseltamivir has been downgraded in the WHO list of essential medicines from a “core” drug to one that is “complementary”—a category encompassing drugs that are deemed less cost-effective. The sad tale behind all this is summarized in a BMJ editorial (published 12 July 2017) entitled “WHO downgrades status of oseltamivir.” This article itself is the culmination of BMJ’s heroic efforts to elucidate the matter.
Indeed, unpacking clinical data for Oseltamivir has been a challenge. In 2009, the highly respected Cochrane Collaboration published a review of neuraminidase inhibitors, including Tamiflu, and the results were hardly awe-inspiring. Some time later, the same researchers would learn of several unpublished trials.
The BMJ led the way in getting Roche to release all the unpublished trials, resulting in the April 2014 article entitled “Multisystem failure: the story of anti-influenza drugs.” Among other things, this work confirms that the drugs have modest benefits, that need to be better weighed against possible harms. It is also less than kind toward most of the agencies involved in the expensive rush to acquire massive stockpiles of them, to the great benefit of the manufacturers.
The July 2017 editorial offers three important take-away lessons:
Firstly, it is vital that all trials be published, and that individual patient data be made available for independent re-analysis. Efforts are under way and deserve our support.
Secondly, money spent stockpiling drugs that are minimally effective is money not spent on other public health priorities. Because diverting these funds causes direct harm to the public, we must demand better evidence to inform these decisions.
Thirdly, belief in the efficacy of Oseltamivir may have led to less research to find truly effective drugs for influenza, again harming the public.
The editorial was written by epidemiologist Mark H. Ebell who also notes that “Withholding these data was a serious breach of research ethics by Roche: suppressing information obtained from patients enrolled in trials of a then experimental drug, who thought that they were contributing to the medical knowledge base.”