In one of my drug-safes there is a quantity of out-of-stock Tamiflu tablets which has been there for over 16 years. I know I should dispose of it but I feel I can’t as it does not belong to me. Rather it is the property of the Department of Health who in around 2008 bought enough stock to treat 80 per cent of the population as part of its flu pandemic preparedness. I also keep it there as a personal reminder of greed and human hubris.
A small fee for holding stock of Tamiflu was agreed back then so that when a highly predicted flu pandemic started, antiviral stock would be in place in community pharmacies to supply to the public and save lives – or so we were led to believe.
Oseltamivir (Tamiflu), a neuraminidase inhibitor, was approved for prophylaxis and treatment of seasonal flu by the US Food and Drug Administration in 1999 and then by the European Medicines Agency (EMA) and the Medicines and Healthcare products Regulatory Agency sometime later. A number of randomised controlled trials, systematic reviews, and meta-analysis, mainly sponsored by the drug’s manufacturer Roche, indicated a favourable efficacy and safety profile. The drug works by blocking the action of the enzyme neuraminidase responsible for viral replication. In this way, the drug should reduce the spread of flu and symptoms, especially illnesss such as a severe respiratory infection (pneumonia) which is the main cause of death in patients with flu.
In 2005 and again in 2009, the fear of pandemic flu encouraged bodies such as the World Health Organisation, the Centers for Disease Control and Prevention, and the EMA to recommend government stockpiling of Tamiflu for use in treatment and prophylaxis of influenza A infection. The cost of stockpiling was not insignificant. In the US it was $1.5 billion and in the UK it was £0.5 billion. So, was this a worthwhile investment?
Influenza A is, and always will be, a threat to public health. Pandemics in 1957 and in 1968 resulted in 20,000 and 30,000 excess deaths in the UK population alone and justifies annual investment in flu vaccination programmes.
Bird flu
There is real concern that the human population may at some time in the future be exposed to a novel strain of the flu virus originating in birds which could be spread person-to-person via the respiratory route. Bird flu is transmitted via the oral-faecal route so when the H5N1 strain can be transmitted to humans it requires very close contact for this to occur. There is no evidence yet of this virus swapping genes with other influenza viruses so that it becomes more easily transmissible between humans. Continuing strict quarantine measures will stop the virus spreading into other species such as pigs where this process might be hastened. Indeed, public health is constantly monitoring viral evolution especially in China and other eastern nations where poultry and other livestock live in close proximity to humans.
In 2005 there was panic following a number of deaths from the H5N1 strain. The prediction was that up to 150 million people worldwide would die from bird flu. In the end only 282 people died from the disease between 2002 and 2009. The modeller was Niel Ferguson who you might remember also modelled deaths from Covid-19 in 2020.
In 2007 John Stone, a UK medical journalist, raised the concern of phoney pandemics following flu hypes. He suggested that scares were being promoted not because of sober assessment of risk but rather because they provide a bonanza for the pharmaceutical industry. He called for better means of telling the difference.
Indeed, Roche made excessive profits from sales of Tamiflu – mainly for government stockpiles – although we cannot discount sales to worried citizens. In October 2005 panic demand for drugs to treat bird flu drove up prices, with drugs also appearing on public auction sites such as eBay, which eventually banned the sale of Tamiflu from its website. Private prescriptions for Tamiflu cost about £50 in Europe so national governments began to purchase stockpiles of the medicine.
Swiss drug manufacturer Roche, in what appeared to be a very responsible intervention, urged consumers not to buy Tamiflu over the internet to avoid the risk of purchasing counterfeit pills. Of course, it was important to control use of the drug to avoid resistant virus. Extensive use of Tamiflu was theoretically being linked to exposing wild waterfowl to enough of the antiviral agent in wastewater to create resistant strains.
The drug’s excreted metabolite, oseltamivir carboxylate (OC), itself the active antiviral, is excreted as OC in urine and faeces. OC withstands degradation through sewage treatment and for several weeks afterward. Birds drinking water from catchments contaminated with OC would ingest the antiviral, which would inhibit non-resistant viruses in the birds’ digestive systems while enabling resistant viruses to proliferate. Birds excreting the resistant virus would spread the strain among other waterfowl at the same body of water.
This risk was shown to be very real in regions of high population such as London. Resistant strains could proliferate within a week if a pandemic started, assuming all patients start taking Tamiflu as soon as they develop symptoms. Pandemic use of the drug had been poorly thought through
Safety and efficacy
In addition, serious adverse events, especially neuropsychiatric events, were being frequently reported and this brought into question the clinical utility of Tamiflu as a pandemic drug that would likely need to be given to many citizens. A Cochrane review and other related articles questioned the risk-benefits of the drug, raising doubts about the regulatory decision of approving it. The recommendation to stockpile the drug was also questioned.
According to data from a Roche-funded meta-analysis study, 29,234 patients from 78 studies of hospitalised patients with flu (H1N1), and who took Tamiflu, reduced the risk of death by 19 per cent compared to no treatment. This benefit increased to 50 per cent if treatment started within two days of flu symptoms.
The Cochrane Collaboration decided to take a closer look at this study. Cochrane reviews are the gold-standard in medicine: They summarise all the data on a given treatment, and they are in a constant review cycle because evidence changes over time as new trials are published. A review in 2008 found some evidence that Tamiflu does reduce the rate of complications of flu such as pneumonia.
Cochrane had summarised the data from all of the trials but its positive conclusion was driven by data from just one of the papers it cited: An industry-funded summary of 10 previous trials. From these 10 trials, only two had ever been published in the scientific literature. For the remaining eight, the only available information on the methods used came from the brief summary in this secondary source, created by Roche. This secondary data was not publicly available so Cochrane had to fight for it.
The full data were finally released in 2013. With all data available it was concluded that oseltamivir (Tamiflu) could reduce the duration of flu symptoms and reduce the proportion of symptomatic cases among infected people. But it did not find evidence that the drug reduced transmission or respiratory complications. These were vital criteria for any pandemic treatment or prophylaxis.
This was a scandal but, if it was ever identified as such, now seems to have been largely forgotten. Roche was not satisfied with the sales of the drug for seasonal flu and according to Cochrane “embarked on a fraudulent campaign to convince the United States to add Tamiflu to its Strategic National Stockpile”. Cochrane told the BMJ, “Roche misrepresented that Tamiflu could stop the spread of an influenza pandemic – when the evidence doesn’t show the drug can even stop viral transmission, let alone prevent complications or deaths.”
Perhaps I will now dispose of my out-of-date Tamiflu stock and just keep one box to remind me that too often we fail to ask the critical questions, or important information is withheld with all too negative consequences.
