Stockpiling in the dark? Tamiflu and the Public Health Agency of Canada

The Government of Canada reported last week that they are working with pharmaceutical manufacturer Roche to release the neuraminidase inhibitor Tamiflu (oseltamivir) from Canadian stockpiles to ensure availability of the drug for a particularly severe flu season in Canada this year. This move was facilitated by the Public Health Agency of Canada (PHAC) and Health Canada in response to higher than expected demand for the drug.

The agency’s Director of Pandemic Preparedness stated that “given that we are still in the midst of influenza season and given that we certainly do not want to have any kind of supply disruption at this point in time, the Public Health Agency Canada … has elected to work with Roche to ensure that there will be no supply disruption.”

The primary maxim of Evidence-Based Medicine- the whole point of EBM, really- is that clinical decisions should be made according to the best available evidence. We don’t profess to know all the evidence behind what should be stockpiled at a national level in Canada or elsewhere. This complex practice requires an enormous amount of evidence review and surveillance data to determine what will (and could) be needed to safeguard a country.

But we do know something about the evidence base for neuraminidase inhibitors, and the recent controversy about Roche’s withholding of clinical trial data on the use of these drugs to treat influenza. Tom Jefferson and colleagues’ 2009 systematic review and meta-analysis of available data is a great starting point, and notes that publicly available studies, taken together, suggest “modest effectiveness of neuraminidase inhibitors against the symptoms of influenza in otherwise healthy adults”. More importantly, though, their study goes on to note that a “paucity of good data has undermined previous findings for oseltamivir’s prevention of complications from influenza” and that “independent randomized trials to resolve these uncertainties are needed.”

When they reviewed the evidence again in 2012, they were unable to access full clinical study reports despite requesting them from the manufacturer. They concluded that “a high risk of publication and reporting biases in the trial programme of oseltamivir” precluded being able to properly assess the evidence of its effectiveness.

Without this data being available, then, the evidence to support using Tamiflu is questionable at best, and certainly not strong enough to justify stockpiling hundreds of millions of dollars of it for national pandemic preparedness.

What has the PHAC done about this? In 2010, the CMAJ reported that the PHAC reviewed the results of the aforementioned systematic review but “the articles published in the BMJ do not change [the] Public Health Agency of Canada’s advice with respect to the use of antivirals with the H1N1 flu virus.”

The BMJ has taken up this issue of missing clinical trial data, and is pressing Roche to release all its data on Tamiflu trials, and clinical epidemiologists are trying to obtain this data to properly analyze it. Only then, will we know if this drug is truly effective, and if the enormous sum spent on stockpiles around the world was worth it.

The Alltrials petition we wrote about last week is another example of an attempt to remove this critical impediment to scientific progress, and ensure all the necessary evidence is available for decision-making.

Ultimately the decision to prescribe is made by a practitioner acting in patient’s best interest. Beyond understanding relevant guidelines and public health recommendations, we encourage individual practitioners to familiarize themselves with the best available evidence to be the best for their patients. As it stands, we’re slightly bewildered as to PHAC’s decision to promote Tamiflu so strongly, and that’s why we encourage individual practitioners to make their own decisions using the best, most recent evidence.

 

-Originally posted on the EvidenceLive blog at http://www.evidencelive.org/blog

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Mammography- more harm than good?

Since its development, mammography has been considered one of the most impressive advances in cancer screening. It is thought of as an essential tool in reducing morbidity and mortality from this highly prevalent disease.

Every woman who has undergone mammography knows the anxiety of waiting for her test results. For most people in this situation, the results are anxiety- relieving, and no further management is indicated. But for a few, the results will mean more tests, and more anxiety. Some of these women will turn out to have invasive breast cancer, and their lives will be saved because of screening. Others will undergo additional testing and it will turn out that they did not have invasive (or potentially invasive) breast cancer, because all screening carries with it the risk of false positives. When the benefits outweigh the harms, screening is justified.

This is why we are so excited to have Peter Gøtzsche- Director of the Nordic Cochrane Centre in Copenhagen and author of Mammography Screening: Truth, Lies and Controversy – speaking at EvidenceLive 2013. He has a different take on breast cancer screening, and is very concerned with the possibility that theharms of mammography outweigh its benefits. According to Gøtzsche, this is a big problem, and one that we should take very seriously in developing health services and deciding what is best for individual patients.

But not everyone supports these findings. Jack Cuzick, Professor at Barts and the London School of Medicine and a leading researcher in cancer screening (having been one of the first to show that tamoxifen reduces the risk of contralateral tumours), recently raised concerns regarding the Cochrane systematic review that supports Gøtzsche’s claims. Cuzick recently asserted that Gøtzsche’s desire to abandon screening altogether “has detracted from efforts to improve breast cancer screening” and has been detrimental to what should be the real goal: to refine and advance screening in order to reduce morbidity and mortality from breast cancer.

Here’s my question to you: What do you think about the role of mammography in modern healthcare?

 

-Originally posted on the EvidenceLive blog at http://www.evidencelive.org/blog

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Autism and vaccination again? Really?

Most readers will be all too familiar with Dr Andrew Wakefield’s absurd, now fully retracted and discredited (the same goes for his medical license, thankfully) 1998 study suggesting a link between autism and vaccination. Dr Wakefield’s science was shoddy, and his conflicts of interest were both remarkable and undisclosed. In short, we feel confident describing this as low quality evidence with a high risk of bias if we have ever seen it. When a ‘researcher’ takes blood samples from guests at his child’s birthday party you know there’s trouble.

Unfortunately, Wakefield’s study was published by one of the highest-impact journals in medicine, and the story took off and became the cause celebre of Hollywood celebrities and pseudo-practitioners. Whereas measles had been all but eliminated and vaccination rates reassuringly high before this, there are now more and more reports of measles outbreaks due to reduced vaccine uptake.

Which is why we find it so disturbing that the New York Times recently ran an article entitled “An immune disorder at the root of autism” .The author, who is noted at the end of the article as having a forthcoming book on the topic (“An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases”), espouses baseless conspiracy theories loosely based on Wakefield’s discredited work, combining it with the “hygiene hypothesis” into a new form of propaganda. He even goes as far as to suggest that there is a “subset of autism–perhaps one third and very likely more—[that] looks like a type of inflammatory disease. And it begins in the womb.” What references, what science to back this up? It’s entirely unclear. Maybe you have to buy the book to find out.

As clinicians, researchers, and patients, we depend on methodologically sound studies to sort out what is effective and what is spurious or harmful. Then, conclusions need to be supported by the data, rather than baseless generalizations and conjectures. If the evidence isn’t there, or people (even unintentionally) mislead the public through overreaching the available evidence, researchers fail to fulfill our obligation to help people make the best choices possible. Effectively communicating evidence to the public for this purpose is a major part of evidence-based medicine.

That’s why we are privileged to have investigative journalist Brian Deer speaking at Evidence Live 2013. He was responsible for bringing forward the truth about Dr Wakefield’s gross scientific misconduct. His work exemplifies the importance of effectively communicating evidence to the people who need it most. If you’re interested in these issues, you should join us.

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Data, data everywhere?

Hidden data, missing data, withholding data- whatever you call it, not all clinical trial data is publicly available, and we think that’s an issue. Regardless of the description, incomplete data is an impediment to ensuring that patients get the best care possible.

At its heart, evidence-based medicine aims to answer one important question: do treatments or tests do more harm than good? When we talk about appraising studies, we are trying to figure out if doing a diagnostic test, or performing an intervention, is going to help a patient more than it will harm them. Medicine is filled with uncertainty; the tools of EBM enable us as researchers, clinicians, policy makers and teachers to get it right, and we hope that as time goes on, we are able to get it right more and more often.

Making a clinical decision when we do not have all the information at hand is risky. Like driving too fast in foggy weather, practicing medicine on the basis of the results of incomplete clinical trial data sets us up for failure. The example of rosiglitazone (Avandia), in which some of the relevant data was withheld at the time of publication and drug approval, is one such example.

Rofecoxib (Vioxx), the ‘blockbuster’ arthritis pain tablet that was supposed to reduce GI bleeding associated with long-term NSAID use, did just that, in Merck’s ”on-treatment analysis”, which hid those who dropped out of the trial. When all the data was analyzed properly, including the dropouts in an “intention-to-treat” analysis, more people died in the rofecoxib group than in the control group, and the reduced GI events were for naught, made up for in spades by the increase in deaths secondary to cardiovascular events.

These are two of many examples of situations in which hidden data has caused harm, and cost lives. This is why the EBM world has been surprised by GSK’s recent announcement pledging to make all clinical trial data fully accessible to the public. The idea is that by allowing people to access all the data, made entirely anonymous, anyone will be able to analyze and investigate the results of clinical trials.

Several of our Evidence Live 2013 speakers are world leaders in this field- Ben Goldacre’s new book Bad Pharma is fast becoming a best-seller and deals with this topic directly- and the discussion should be lively and controversial when we come together in Oxford at the end of March 2013 for the conference.

For what it’s worth, we applaud the promise; it’s the sort of thing Archie Cochrane was talking about 40 years ago when he set out the challenge to set up a comprehensive repository of clinical trial evidence. But if history tells us anything, we’ll believe it when we see it.

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Forcing the spring towards a new era in evidence-based medicine

“But, by the words we speak and the faces we show the world, we force the spring.”

The beginning of Bill Clinton’s first inaugural address seems an odd place to start a discussion about epidemiology, I admit. For us, though, it reflects the developments over the past few months that have changed how evidence-based medicine is practiced, and how it’s going to look in the near future. And we’re excited about all of it.

It’s no secret that there is massive pressure on drug companies to fundamentally change how they operate. This push for a new era of accountability is due to the efforts of many people, including Ben Goldacre, whose Bad Pharma has become an international phenomenon, and Tom Jefferson and Peter Doshi, whose campaign to obtain all the data on Tamiflu has been a major driver towards exposing withheld data. The current state of pharmaceutical research is a little like when you were in school doing an experiment, and something didn’t quite turn out right, and you ‘forgot’ to write down the results for that one part of the experiment. It may have worked in high school, when the worst that could happen is that you would have to stay after class. But when billions of pounds and thousands of lives are at stake, the stakes are quite different.

The All Trials campaign- an online petition that’s rapidly gaining publicity and support- now has over 25000 signatures, including major medical journals (our EvidenceLive partner, the BMJ, is one of the instigators of the campaign). Last week, pharmaceutical giant GSK signed on – an incredible step in the right direction for an industry that continues to be, in large, stuck in the dark ages when it comes to transparency.

This week, another campaign has started to heat up, this time questioning how guidelines are developed and where the incentives lie in their creation. Bad Guidelines has initially targeted the “Guidance on collaboration between healthcare professionals and the pharmaceutical industry” as a particularly egregious example of a document that august institutions, such as the UK Department of Health, have signed on to and probably shouldn’t have. At the very least, one wonders if they read it through before signing up.

The philosopher Thomas Kuhn suggested that the history of scientific progress has been one of paradigm shifts, in which research continues along in a certain paradigm until someone comes along to break out and move on to another radically different way of looking at phenomena. We can’t help but wonder if we are in the midst of a paradigm shift in healthcare- one that values transparency, scientific progress, and responsibility to patients above all else. If you haven’t already signed up, come to EvidenceLive, and help “force the spring” towards a new era in evidence-based medicine.

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