Tamiflu & Relenza trial exposes systemic failures. What next for the medical profession?

A major study by Cochrane reviewers published this week in the BMJ brings into question the system of drug regulation and evaluation. In the culmination of a four year fight to get hold of previously unpublished data from industry, Tom Jefferson and his colleagues have published their review, which shows that the evidence that led to the worldwide stockpiling of Tamiflu (oseltamivir) and Relenza (zanamivir) was incomplete and biased. ^{1, 2}

This raises serious questions for all involved, but particularly for practicing clinicians upon whom it is incumbent to demonstrate their probity. This is essential for our patients and the public to maintain their trust in the profession and there is now a groundswell of opinion that to achieve this, we should be transparent in declaring our interests.

Neuraminidase inhibitors, mainly Tamiflu (produced by Roche) and Relenza (produced by GlaxoSmithKline) are a group of drugs that had been shown in a previous Cochrane review, published in 2006, to have some effectiveness in treating influenza in healthy adults and children. Prior to 2009, sales of these drugs were minimal, but their use increased dramatically with the spread of the influenza A/H1N1 (swine flu) epidemic. Governments worldwide rushed to stockpile the medicines. The UK Department of Health spent £560 million between 2006-7 and 2012-13 and the US has spent more than $1.3 million.

A recent report by the House of Commons Public Accounts Committee said that despite there being only limited evidence, the business case developed by the Department of Health assumed that Tamiflu would give a 40% to 50% reduction in complications and mortality. This assumption was based on advice from a range of experts including the Department’s Scientific Pandemic Influenza Advisory Committee. 

However, it has since become clear that the previous Cochrane review was based on 10 clinical trials, all of whom were supported by Roche, with only two published in medical journals.

Over the past four years in what the editor-in-chief of the BMJ, Dr Fiona Godlee, has described as a ‘cat-and-mouse’ fight, the Cochrane authors together with the BMJ and Channel 4 News, have pushed the drug companies for access to the trial data. Eventually, in April 2013, GSK released their raw data, with Roche following three months later giving the researchers over 150,000 pages of data to analyse. 

Their conclusions raise big questions for the regulators, the pharmaceutical industry, policy makers and for patients and doctors. It now appears that the original evidence was incomplete and the benefits were overplayed. In the new study, Jefferson and colleagues’ main findings are that: 

1. The use of Tamiflu reduced the duration of influenza-like symptoms by only half a day in adults, with no effect in asthmatic children;

2. There was no evidence of a reduction in hospitalisations or serious complications such as pneumonia. In 14 out of the 20 trials, pneumonia was only a self-reported measure and in the 2 trials that used x-ray confirmation of pneumonia, no effect was seen;

3. There was little evidence that the drugs slowed down progression of the illness and is probably ineffective at preventing person to person transmission;

4. There was an increased risk of nausea and vomiting in adults by 4% and children by 5%, and an increased risk of psychiatric events.

In addition, some of the trials had serious methodological flaws such as the placebo capsules being a different colour to the active capsules.

Carl Heneghan, one of the authors of the trial, concludes that there is no credible way in which neuraminidase inhibitors can prevent a ‘flu pandemic with many of the trials showing that these drugs are no better than over-the-counter (OTC) medications such as paracetamol.

What should we now think? How can patients make decisions about their treatments knowing that the pharmaceutical industry deliberately withholds unfavourable data? What other drugs and interventions that have been licenced, and will continue to do so, should we question?

As a doctor, I rely on the evidence presented to me to make decisions about the risk-benefit ratio of giving my patients various treatments. I clearly remember working in an intensive care unit in 2009 and being told that early treatment with Tamiflu would help prevent complications in patients with swine flu. However, this study now questions my belief in the systems that are in place to regulate and evaluate drugs and on the decisions that are based.

Fiona Godlee says that the system is broken and has been designed to satisfy the needs of the manufacturers rather than patients. There is an irreducible conflict of interests in the way that drugs are evaluated and regulated, borne out of the pharmaceutical industry’s duty to their shareholders.

It is easy to have sympathy with the government’s position in 2009, in the face of the WHO predicting 700,000 deaths in the UK. Had they not stockpiled the drug, as happened in Poland, and the swine flu pandemic was as devastating as some predicted, then they would have faced massive criticism. However, now knowing what they do from a government funded study, surely it would be irresponsible to spend another £50 million on the drugs, as has been mooted?

Our patients look to us, as doctors, for advice and guidance. Many of us are influenced at some points in our careers by industry, whether it be through free lunches, pens, post-it notes, right up to the funding of clinical studies. In fact, the Association of the British Pharmaceutical Industry has estimated that the drug industry pays £40 million a year to doctors for speaking fees, flights, hotels, and other travel expenses. At present, declaration of these interests is subjective and relies on a system of trust. How can we reassure patients that the decisions that we make with them is made with only their best interests at heart?

For me, it comes down to exactly that. Trust. This is an essential ingredient of leadership and of relationships.  It is well known that the medical profession is still one of the most trusted but we can not rest on our laurels. We need to earn and maintain the trust of our patients in the same as we, as doctors, need to be able to trust the organisations and systems that exist to protect the patients.

In the case of Tamiflu and Relenza, it is clear that there are serious flaws in the system that need urgently  addressing. I feel that it is incumbent upon us, as medical professionals, to question all the evidence that we are presented with in order that we fulfil our duty to our patients. Also, we need to be open and transparent and that is why I fully support the http://www.whopaysthisdoctor.org website which is a voluntary register of interests. I’ve signed up - I can’t think of a reason why anyone wouldn’t.

For more information, go to http://www.bmj.com/tamiflu

Dr Marc Wittenberg

National Medical Director’s Clinical Fellow at NHS England & BMJ

@DocMarcW