Inside Politics

Tamiflu marketing exposes holes in drug regulatory regime

When fears about an avian flu and then an H1N1 pandemic struck in 2009, Canadians were understandably searching for ways to protect themselves. Enter Tamiflu, a drug that its maker, Hoffman La-Roche, and its advocates, claimed reduced complications and hospitalizations and prevented deaths.

The problem with those claims, according to critics that include the esteemed British Medical Journal, is that they aren't supported by scientific evidence.

And as the federal government and its provincial and territorial counterparts get ready to spend millions more to replace Canada's expiring stockpile of Tamiflu, now might be a good time to begin asking tough questions of the company, the individuals promoting the drug and Health Canada, which considers the drug to be of "modest" benefit.

Radio-Canada's Enquête, in a joint investigation with RSI (Swiss Italian Television) and National Public Radio in the United States, asked those questions last month in a documentary about Tamiflu. An English-Language version ran Monday on The National.

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The Enquête report raised several issues that bear a closer look.

Is Tamiflu as effective as the company claims?

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. So if the regulator characterizes Tamiflu as having a modest effect in reducing symptoms, then how could the company make greater claims?

This question generated controversy in the scientific community.

Independent experts called the Cochrane Group wanted access to all of the Roche's clinical trial data that it submitted to regulators. The group published an analysis in the British Medical Journal, urging Roche to release the data.

As a result, the company promised to make the studies available, but it still held back some data. Roche uploaded the data to its password-protected website that was only available to health researchers.

CBC News asked Barbara Mintzes, a pharmacology professor at the University of British Columbia, to obtain the partial data Roche had released from the eight unpublished studies. CBC then analyzed that data in conjunction with Mintzes, who concluded that there was insufficient evidence to support the company's overall claim that the flu drug reduces complications. In Mintze's view "it was a waste of money to stockpile Tamiflu."

This, despite the endorsement from experts, including Allison McGeer at Toronto's Mount Sinai Hospital, who said Canada was right to stockpile the drug despite its high cost. McGeer said having easy access to the drug was still "worthwhile insurance."

McGeer's colleague at the hospital, Donald Low, also supported stockpiling the drug, despite the lack of solid, clinical evidence. "So we're making a leap of faith that what we saw on the test tube and with the very limited data we had clinically that this would.... result in a decrease death rate, and decrease complications and decrease hospitalizations," Low told Enquête in an interview.

The company also argued that in addition to clinical trial evidence, there have been many so-called "observational studies" that prove the drug's effectiveness and safety. But the BMJ has challenged the validity of those studies, too.

To date, neither Health Canada, nor the U.S. Food and Drug Administration has changed its mind about the drug's effectiveness.

Concerns raised about potential dangers

On Nov. 29, 2006, Health Canada issued a warning on its website: "Health Canada is informing Canadians of international reports of hallucinations and abnormal behaviour, 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 behaviour. Health Canada has not received any such reports in Canada and is continuing to actively monitor adverse events reported for Tamiflu."

The alert conceded that there had been seven reports of psychiatric adverse behavior, but those reports were only found in elderly patients. However, a CBC News analysis of the department's online adverse drug database uncovered suspected psychiatric reactions in individuals ranging in ages from 30 to 52 between the years 2001 and 2004.

The next year, 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 behaviour in Japanese children or teenagers taking Tamiflu."

The warning letter, drafted by Roche, claimed that, to date, there were no similar reports in Canada. The CBC News analysis of Health Canada's online adverse drug reaction database turned up examples of such side effects before and after the 2007 warning letter was published. For instance, in 2001 there was a report of "agitation." In 2003, a report of "altered state of consciousness." And in 2004; two reports of "delusion."

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 same year, there were also reports of "acute psychosis," "Aggression" and "Delirium." By Health Canada's own estimation, only about one-tenth of adverse reactions are reported to the department. So the actual numbers could be higher than the instances that appear in the regulator's database. The adverse reaction reports don't necessarily mean the drug is to blame, but the side-effects should least be a signal for Health Canada to investigate these rare occurrences. It's unclear whether that ever happened.

Dr. Peter Silas, a pediatrician based in Utah, told Radio-Canada's Enquête that some of his patients exhibited symptoms of abnormal behaviours. 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."

By then, hundreds of cases had already been reported in Japan, including accidental deaths. A CBC News analysis of the U.S. Food and Drug Administration adverse drug reaction reports obtained through that country's freedom-of-information law also produced 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."

It's often difficult to establish a clear, causal link between a drug and rare adverse reactions like these. Roche's Dr. Stephen Toovey said the delusions patients experienced while suffering from a high fever were caused by the flu itself, not the drug, a view echoed in Health Canada's warning letters. But some of Dr. Silas' patients who had taken the drug and displayed the altered condition didn't have a fever.

Questions about conflicts of interest

Allison McGeer and Donald Low are two of the many experts who made public pleas to stockpile Tamiflu. What people might not know is that both had financial ties to Roche. Although the federal government knows that at least some of the experts it consults for advice have such ties, the department does not make the information public.

As the Enquête piece reported, Low is on Roche's advisory board, is a member of the company's speaker's bureau and has promoted Tamiflu on TV. Low says there is nothing wrong with this and stands by his recommendation. "I do a lot with the industry and it doesn't take too long to catch up to you if you are making statements that in your heart you don't believe and you don't have data to support," he told Enquête.

McGeer has also been quoted discussing Tamiflu's benefits. And she, too, has ties to the drugmaker, consulting for them and sitting 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. McGeer says she listens to opinions on all sides of the debate, and says she is not involved in promoting the use of Tamiflu. But here's what she had to say in a video about Tamiflu produced by Roche:

"One of the new things about influenza is the availability of antiviral medications, actually medications that kill virus and make you feel better faster when you have influenza. They're very effective at making you feel better faster and preventing you from becoming seriously ill or getting complications, but the catch to them is that for them to work you have to take them early," McGeer says in the company video.

"That means if you get something that you think is influenza, you need to see your doctor within two days of getting sick, and then you need to ask him or her whether it is influenza, and whether the antivirals might help you."

After being shown the video segment by Enquête, McGeer agreed it could be seen as marketing, and said it was something she might not do again, but added that "some of it is about getting information to people about the drugs."

"I don't think that doing one promotional video is something that is . . . I don't think I'm that important, okay, on the scale of things, about deciding about antivirals," she said.

But UBC's Barbara Mintzes says these ties, especially membership on speakers' bureaus, are important because they indicate that the experts are valued "as long as their message is positive for the marketing team."

For his part, the chief public health officer of the Public Health Agency of Canada, David Butler-Jones, sees nothing wrong with these drug company ties, as long as he has access to exprerts who possess a variety of opinions.

McGeer and Winnipeg flu expert Fred Aoki belong to committees that advise the agency on anti-flu drugs like Tamiflu.

Butler-Jones says it's well-known that they've worked for the company because they must declare that fact. "They're part of a process that we have," Butler-Jones told Radio-Canada. "If we are going to get the best scientific advice possible, we are not going to restrict ourselves to only those who have no link to anybody."

Still, Butler-Jones conceded that perhaps it was time to re-visit the agency's conflict-of-interest guidelines. The Public Health Agency of Canada said over the weekend it is a looking at that issue, following the Enquête investigation.

He might begin by making public more information about the advisory committees, including the list of members and their conflicts of interest. The U.S. health authorities like the Centers for Disease Control and the Food and Drug Administration routinely make this information available.

CBC News asked the Canada Public Health Agency to produce this information. Initially, the agency refused, but Butler-Jones has left the door open.

"I have no issue with this. It's not been part of our processes to this point... now is actually a good time to look at that."

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