Don’t miss the first part of this article, Is Tamiflu Safe & Effective? Cochrane Review vs. Roche Pharma.
Adverse psychiatric side-effects: The new Cochrane review also said it scoured through raw data and found more reports of possible side effects, like headaches and psychiatric problems, than were mentioned in published papers describing clinical trial results, the New York Times reports.
Roche, in its statement sent in response to a query by the Times, said side effects were listed on the drug’s labels. The adverse psychiatric effects are well known to health regulators.
Japanese health authorities were the first to issue a warning that Tamiflu should not be given to teenagers, after reports in 2004 that some Japanese children who took the drug exhibited bizarre behavior.
In 2008, the U.S. Food and Drug Administration changed the drug’s label to acknowledge reports of “delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes,” among flu patients taking Tamiflu.
The move followed a 10-month review by the FDA, which found 103 cases of “neuropsychiatric adverse events,” including the deaths of a 17-year-old boy who was killed after jumping in front of a truck and a 14-year-old boy who fell after climbing on a balcony railing.
More than two-thirds of the 103 cases occurred in children, and most were in Japan, then the biggest consumer of Tamiflu. It is unclear whether the psychiatric problems were a side effect of the drug or the flu.
Inconsistencies in data
Setting out to test the drug maker’s claims, the Cochrane researchers first sought data from Roche itself. But when the company refused to provide all of its trial data for analysis, the team obtained some clinical study reports from the European Medicines Agency (EMA).
The team then compared published data with more complete unpublished clinical trial records. It found inconsistencies between the published and unpublished data—in terms of the serious adverse events and disparities in the numbers of flu-infected people in the treatment and control groups, reveals author Dr. Tom Jefferson, a Cochrane epidemiologist based in Rome.
“The disparity is important because in oseltamivir trials, primary efficacy outcomes were analyzed on the influenza infected subpopulation, but it is not clear that these groups were in fact comparable,” Jefferson said in a release sent to CBC News Canada.
The new review included data on 60 percent of the patients in the clinical trials of Tamiflu had never been published in medical journals.
“If we look only at published reports, the extreme danger is that we are going to arrive at conclusions that are biased and that nobody should trust,” Dr. Peter Doshi, a postdoctoral fellow at the Johns Hopkins University School of Medicine and a co-author of the new review told Andrew Pollack, New York Times health writer.
Roche refused to provide data
The reviewers also said that their analysis was held back by the fact that the drug’s maker, Roche, had not supplied all the data from clinical trials that it had promised to provide.
“To this day, we have not received a single full study report from Roche,” Dr. Doshi told the New York Times. He said that this was not reasonable since it’s not Tamiflu’s “secret formula” they’re after but the full details of what happened in the clinic trials.
The Cochrane Collaboration has reviewed the evidence on Tamiflu in the past, and it has clashed with Roche before over access to data. The new review was financed by the U.K.’s National Institute for Health Research.
In its separate probe, BMJ also raised serious concerns about access to drug data, the use of ghost writers in drug trials, and the drug approval process.
The BMJ investigation showed that because different regulators took different approaches to the data submitted to them, this led to conflicting messages about Tamiflu’s effectiveness.
For example, the European Medicines Agency released some of the reports of Tamiflu clinical trials to Cochrane, but it admits that it did not ask for the remainder from Roche, although it was legally entitled to do so.
The EMA has since told the BMJ that it plans to start publishing reports for all drugs submitted for approval in the next few years.
“We hope very much that the EMA will indeed take this important step in making the full study reports available,” says Dr. Fiona Godlee, BMJ editor-in-chief. “But we are still a long way away from having a full trial history for all drugs in clinical use. Public safety and the proper use of public money demands that we should stop at nothing less than this.”
Affects antibody production
Both the Cochrane and BMJ analyses also raise questions about Tamiflu’s clinical effects.
Cochrane’s meta-analysis also found that Tamiflu appears to affect antibody production—a claim that Roche refutes. This is vital, say Cochrane, because influenza vaccination relies on an antibody response to be effective. But when queried by the BMJ, Roche refused to explain how the drug works.
This lead the Cochrane team to conclude: “We believe that until more is known about the mode of action of neuraminidase inhibitors health professionals, patients and other decision makers need to reflect on the findings of this review before making any decision about the use of the drug.”
Business as usual
So far, the U.S. FDA, UK’s NHS and Health Canada have not said anything about changing their stand on the drug’s effectiveness.
The FDA, which is reported to have reviewed the Tamiflu trial program in more detail than anyone outside of Roche, has chosen not to review the largest ever trial of Tamiflu when considering the drug for approval. It states that “Tamiflu has not been shown to prevent such complications (serious bacterial infections).”
The US Centers for Disease Control and Prevention (CDC) continue to cite key published trials of Tamiflu, claiming a reduced risk of influenza complications, even after Roche admitted that some of these trials have been ghost written, the BMJ reports.
Dr. Godlee criticizes this situation, saying: “The discrepancies between the conclusions reached by different regulators around the world highlights the absurd situation we find ourselves in.”
“In a globalized world, regulators should cooperate and pool their limited resources, Dr. Godlee says. “Otherwise we will continue to waste money and risk people’s health on drugs that don’t work.”
Health Agency said it is aware of the publication and is reviewing it closely.
“This review comments on the effectiveness of antivirals for the prevention and treatment of influenza in healthy adults and children,” said Sylwia Gomes, Health Canada spokeswoman. “It does not address the effectiveness of antivirals for the treatment of pandemic influenza, particularly in individuals at high risk of complications due to influenza, such as pregnant women, young children, individuals with chronic medical conditions and others.”
“Multiple observational studies conducted during the 2009 H1N1 pandemic have supported the effectiveness of antivirals in minimizing illness and deaths from pandemic influenza,” Gomes said.
“That’s why the stockpiling of antivirals is an essential component of the Canadian Pandemic Influenza Plan,” she added.
The WHO will keep Tamiflu on its list of essential drugs, Gregory Hartl, a spokesman for the Geneva- based agency, said.
The WHO doesn’t dispute the 21-hour figure, Hartl said. But apart from just focusing on clinical trials, the agency also looks at evidence collected on the ground during flu outbreaks, he said. “Cochrane is looking at apples, and we are looking at apples and oranges,” he claimed.
Cochrane recounts that previous evidence suggesting that Tamiflu was effective against flu complications came from combining the results of 10 clinical trials into a meta-analysis, which was then published in 2003.
Based mainly on this 2003 meta-analysis, the Cochrane Collaboration in 2006 concluded that Tamiflu could reduce flu complications.
But when a reader pointed out that only two of the 10 studies included in the meta-analysis had been independently published, Cochrane researchers reviewed those two studies in 2009. It found that when it relied only on those two published studies, there was no solid evidence that Tamiflu reduced complications.
For the latest analysis, the group decided not to rely on published papers and to instead rely on rather raw data from clinical trials. It received thousands of pages, mainly from the European Medicines Agency.
Meanwhile, Cochrane postponed its analysis of zanamivir, for which it had 10 trials, because the drug’s maker GlaxoSmithKline, offered individual patient data. The group said it wanted time to analyze the data.
As expected, Basel-based Roche insists that it provided ample information for Cochrane’s analysis.
“Roche provided the Cochrane group with access to 3,200 pages of very detailed information, enabling their questions to be answered,” a spokesman told swissinfo.ch.
“Extensive clinical research and real-life experience show that Tamiflu has a generally good safety and tolerability profile.”
An independent investigation carried out by Canada’s CBC news agency showed that Health Canada may have downplayed the adverse psychiatric effects of Tamiflu. It also discovered that health experts who made public pleas to stockpile the antiflu drug in Canada had undisclosed financial ties to Roche.
On Nov. 29, 2006, Health Canada issued a warning on its website: “Health Canada is informing Canadians of international reports of hallucinations and abnormal behavior, including self harm, in patients taking the antiviral drug Tamiflu. These reports include children and teenagers, primarily from Japan. While the connection with the drug in these cases has not yet been proven, high fever or other complications of influenza can affect mental state, which in turn can lead to abnormal behavior. Health Canada has not received any such reports in Canada and is continuing to actively monitor adverse events reported for Tamiflu.”
While the alert agreed that there had been seven reports of psychiatric adverse behavior, it said those had happened only in elderly patients.
But according to David McKie of CBC News, his own analysis of Health Canada’s online adverse drug database bore data of suspected psychiatric reactions in people ranging in age from 30 to 52 from the year 2001 to 2004.
David McKie is an award-winning journalist who uses access-to-information and computer-assisted reporting in many of his stories.
On March 27, 2007, Health Canada, published another warning letter to “inform Canadians that the Canadian labeling for Tamiflu has recently been updated to include new safety information resulting from adverse reaction reports of abnormal or suicidal behavior in Japanese children or teenagers taking Tamiflu.” The warning letter claimed that there were no similar reports in Canada. The letter was drafted by Roche.
But McKie says his analysis of Health Canada’s online adverse drug reaction database also turned up examples of such side effects before and after the 2007 warning letter was published. In 2001 there was a report of “agitation,” in 2003, a report of “altered state of consciousness,” and in 2004; two reports of “delusion,” the reporter writes.
In 2009, the year of the H1N1 pandemic fear when the most Tamiflu was sold, there were at least 10 instances of “abnormal behavior” that were reported to Health Canada. That year, there were also reports of “acute psychosis,” ”aggression” and “delirium.” The actual numbers could be higher than the instances that appear in Health Canada’s database, but only about one-tenth of adverse reactions are reported to the department, says McKie.
McKie also analyzed U.S. Food and Drug Administration adverse drug reaction reports, which he obtained through that country’s freedom-of-information law. The analysis also showed descriptions of psychiatric problems, including this one: “My 4-year-old son was given Tamiflu (…) He appeared to have extreme anger and tried multiple times to hurt his two-year-old brother, twice attempting to push him down the stairs.”
Dr. Peter Silas, reported that some of his patients exhibited symptoms of abnormal behaviors. He recalled one patient “hearing whispering voices that he couldn’t decipher…He seemed a lot more anxious and agitated than he had been before taking Tamiflu.”
Hundreds of cases had already been reported in Japan, including accidental deaths, McKie notes.
The drug may not be to blame, but the reported side effects should at least be a signal for Health Canada to investigate these rare occurrences, the reporter says, lamenting, “It’s unclear whether that ever happened.”
Conflict of interest
McKie’s report also revealed financial ties between health experts and the drug maker: “What people might not know is that both health experts who made public pleas to stockpile Tamiflu in Canada had financial ties to Roche,” he says.
According to the reporter, Canada’s Allison McGeer, who has been quoted discussing Tamiflu’s benefits, has ties to the drug maker. She consults for them and sits on their advisory boards, as she does for other pharmaceutical companies. She was also on the speaker’s bureau of Gilead, the creator of Tamiflu.
Donald Low is on Roche’s advisory board, is a member of the company’s speaker’s bureau and has promoted Tamiflu on TV, McKie said.
According to CBC, when Health Canada was approving the drug back in 1999, it was less than enthusiastic. In a heavily-censored document called “Pre-Clinical & Clinical Evaluation Report” that CBC News obtained through access to information, there was a tepid endorsement: Tamiflu’s effect was judged to be “modest.”
“Health Canada’s recommendation says nothing about reducing complications, hospitalization or saving lives, claims that Roche and supporters of the drug make,” says McKie.
“So if the regulator characterizes Tamiflu as having a modest effect in reducing symptoms, then how could the company make greater claims now?” he concludes.