April 10, 2014
No Evidence That Tamiflu Reduces Flu Complications, ER Admissions
Lawrence LeBlond for redOrbit.com - Your Universe Online
Tamiflu is widely used to help patients relieve symptoms of influenza. While the drug – generically known as oseltamivir – can shorten symptoms by about half a day, there is no good evidence to support claims that it reduces admissions to the ER or complications of influenza.
There had been evidence in treatment trials that patients using Roche’s Tamiflu had an increased risk of suffering from nausea and vomiting. Furthermore, when the drug was used in prevention trials, there was an increased risk of headaches, psychiatric disturbances and renal events. And while there is some preventive evidence that the drug can reduce the risk of people suffering from symptomatic outcomes, it has gone unproven that it can stop people from carrying the virus and transmitting it to others.
The review has also found no evidence to back up the claims that GlaxoSmithKline’s Relenza keeps influenza complications and/or hospital admissions down.
The report, titled “Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children,” is based on reports of 20 Tamiflu and 26 Relenza trials. In total, these trials involved more than 24,000 people and the findings challenge the historical assumption that neuraminidase inhibitors are effective in fighting the flu.
The report also finds that there are insufficient grounds to support the use of Tamiflu in preventing the spread of influenza, raising further questions about the most effective way to support drug regulation and public health policy decision-making.
The claims about the efficacy of Tamiflu were a key factor in decisions by governments to stockpile the drug in case of a pandemic. In the US, more than $1.3 billion has been spent on building a strategic reserve, while the UK has spent $710 million for a stockpile of about 40 million doses.
The Cochrane Collaboration questioned the decisions to stockpile the drug in 2009, but because of lack of access to available trial data, its efforts were hampered. Cochrane and BMJ use the new report to issue a call to governments and health policy decision makers, asking, in the light of the latest findings, would you make the same recommendations to stockpile Tamiflu today?
In adults, trials showed that taking Tamiflu led to an alleviation of flu-like symptoms by just a half day (from seven days to 6.3 days); in children, the effects were not as clear. The trials showed there was no reduction in the rate of hospitalizations or serious complications – including pneumonia, bronchitis, sinusitis or ear infection – in adults or children when using Tamiflu. The drug also increased the risk of nausea and vomiting in adults by around four percent and in children by five percent. Psychiatric events also increased by about one percent in those who used Tamiflu. And furthermore, the drug also prevented some patients from producing sufficient numbers of their own antibodies to help fight infection.
With the worldwide outbreak of H1N1 virus (Swine Flu) in 2009, Tamiflu was catapulted into the spotlight, with its use rising dramatically to help combat the pandemic. Initially, it was believed that Tamiflu would reduce the overall number of hospital admissions and complications related to the flu, but the original evidence presented to world governments at the time was incomplete.
The report, which has now benefited from access to more complete reports of original research from the drug manufacturers Roche and GSK, provides a more complete picture for worldwide governments to base new decision making policies on.
“We now have the most robust, comprehensive review on neuraminidase inhibitors that exists. Initially thought to reduce hospitalisations and serious complications from influenza, the review highlights that Tamiflu is not proven to do this, and it also seems to lead to harmful effects that were not fully reported in the original publications. This shows the importance of ensuring that trial data are transparent and accessible,” Dr David Tovey, Editor-in-Chief, Cochrane, said in a statement.
“Drug approval and use cannot be based on biased or missing information any longer. We risk too much in our population’s health and economy. This updated Cochrane review is the first time a Cochrane systematic review has been based only on clinical study reports and regulator’s comments. It is the first example of open science in medicine using full clinical study reports available without conditions. And therefore the conclusions are that much richer. We urge people not to trust in published trials alone or on comment from conflicted health decision makers, but to view the information for themselves,” said the authors of the review, which include Dr Tom Jefferson, Dr Carl Heneghan and Dr Peter Doshi.
However, the drug manufacturers sharply disagree with the findings in the latest Cochrane review.
Roche said, “we disagree with the overall conclusions" and warned they could "potentially have serious public health implications," according to a BBC report.
Dr. Daniel Thurley, Roche’s UK medical director, told the BBC’s James Gallagher that the “definitive piece of research stands as the randomized control trials, which were shared with the regulators, which led to them in 100 countries around the world approving Tamiflu for treatment and prevention of flu."
He said the Cochrane Collaboration had used the wrong statistics, which "systematically underestimate the benefits" of the drug, and used "unorthodox" methods to analyze the side-effects.
"One of the challenges we have here is actually knowing what they've done," he concluded.
In a statement to USA Today, Relenza maker GSK said, "We continue to believe the data from Relenza's clinical trial (program) support its effectiveness against flu and that when used appropriately, in the right patient, it can reduce duration of flu symptoms."
Prof Wendy Barclay, an influenza virus researcher at Imperial College London, said in an interview with BBC News that “Tamiflu works as well as any drug we have now or [that] is on the cards.”
"Yes, I think they should replenish the stockpile. What else can you do if a pandemic strikes? We won't have a vaccine for the first six months," she warned. "If it works a little bit in season flu, the chances are they'll work quite a lot better in a pandemic situation and get more people back to school and work."
Global health experts have mixed opinions on the matter.
The World Health Organization classes Tamiflu as an essential medicine. "We welcome a new and rigorous analysis of available data, and look forward to consideration of its findings after it appears."
The Food and Drug Administration, however, has approved Tamiflu in the US with the exception that the label maintains that the drug “has not been shown” to prevent serious bacterial complications like those associated with pneumonia and other upper respiratory infections. This goes against the original fact that “contradicts the assumptions that were made when stockpiling occurred.”
In 2012, after reviewing an earlier Cochrane report that raised similar questions about the efficacy of antiviral medications, the Centers for Disease Control and Prevention did not change its recommendation on the use of antiviral drugs, calling them “an important adjunct in the prevention and treatment of influenza,” as cited by USA Today’s Michelle Healey.
"We carefully review all available data including randomized controlled trials and observational studies when making recommendations. There is a substantial and growing number of observational studies that show the clinical benefit of antiviral treatment of seasonal and pandemic influenza," The CDC said in response to Cochrane’s latest review.
Still, the Cochrane review clearly recommends that guidance on the use of oseltamivir and zanamivir in the prevention or treatment of influenza should be revised to take account of the evidence of small benefit and increased risk of harms.
“This review is the result of many years of struggles to access and use trial data, which was previously unpublished and even hidden from view. It highlights with certainty that future decisions to purchase and use drugs, particularly when on a mass scale, must be based on a complete picture of the evidence, both published and unpublished,” Dr Fiona Godlee, Editor-in-Chief, BMJ, said in a statement.
“We need the full data from clinical trials made available for all drugs in current use. With the new European Clinical Trials Directive bringing in rules for future drugs, it highlights the enormous challenge we face. We need the commitment of organizations and drug companies to make all data available, even if it means going back 20 years. Otherwise we risk another knee-jerk reaction to a potential pandemic. And can we really afford it?” she added.