by Shannon Brownlee and Jeanne Lenzer

December 10, 2009

from TheAtlantic Website

 

 

 

Shannon Brownlee is a senior research fellow at

the New America Foundation and the author of Overtreated (2007).

Jeanne Lenzer is an investigative journalist and a frequent contributor

to the British medical journal BMJ.

 

 

 

Two months ago, we pointed out in our story on flu in The Atlantic that the antiviral drug Tamiflu might not be as effective or safe as many patients, doctors, and governments think.

 

The drug has been widely prescribed since the first cases of H1N1 flu surfaced last spring, and the U.S. government has spent more than $1.5 billion stockpiling it since 2005 as part of the nation’s pandemic preparedness plan.

Now it looks as if our concerns were correct, and the nation may have put more than a billion dollars into the medical equivalent of a mirage. This week, the British medical journal BMJ published a multi-part investigation that confirms that the scientific evidence just isn’t there to show that Tamiflu prevents serious complications, hospitalization, or death in people that have the flu.

 

The BMJ goes further to suggest that Roche, the Swiss company that manufactures and markets Tamiflu, may have misled governments and physicians. In its defense, Roche stated that the company,

“has never concealed (or had the intention to conceal) any pertinent data.”

The BMJ’s investigation began innocently enough, with an update of a review by the Cochrane Collaboration, a widely-respected international consortium of researchers who periodically examine the medical literature to assess the safety and effectiveness of various treatments.

 

Roche has claimed that its drug reduces hospital admissions by 61% in patients who were otherwise healthy before they got the flu. It has also said that Tamiflu reduces such complications as bronchitis, pneumonia, and sinusitis by 67%, and lower respiratory tract infections requiring antibiotics by 55%.

 

A 2006 Cochrane review of Tamiflu came to similar conclusions - based largely on a paper that looked at ten studies, all of them funded by the company.
 

 


The dog ate my homework

But when the Cochrane team, led by Chris Del Mar, from Bond University in Australia, re-examined the studies they had previously used in 2006, they found some discrepancies.

 

It turned out that only two of the ten studies had ever been published in medical journals, and those two showed the drug had very little effect on complications compared to a dummy pill, or placebo. So the Cochrane reviewers decided to look at the data for themselves.

First they went to the lead authors of the published studies - the researchers who were supposed to have access to all of the data. One author said he had lost track of the data when he moved offices and the files appeared to have been discarded. The other said he’d never actually seen the data himself, and directed the Cochrane team to go directly to the company.

Four months and multiple requests later, the Cochrane researchers had a hodgepodge of data from the company, including two studies that showed the drug was ineffective, but which the company had never published.

 

Roche also provided data from a third study, which involved 1,447 adults and adolescents aged 13-80, the largest study of the drug ever conducted.

 

Yet the company never published that one either. (A summary of this and other studies is available at www.roche-trials.com). But with only partial data, the Cochrane team couldn’t even figure out what the study had been intended to measure.

In the meantime, two former employees of Adis International, a large communications company, came forward with documents showing they had ghostwritten some of the published studies of Tamiflu.

 

One of the ghostwriters told the BMJ,

“The Tamiflu accounts had a list of key messages that you had to get in. It was run by the [Roche] marketing department and you were answerable to them. In the introduction... I had to say what a big problem influenza is. I’d also have to come to the conclusion that Tamiflu was the answer.”

 


Stockpiling

The Cochrane team eventually concluded that the evidence that Tamiflu reduces complications, hospitalizations, or deaths is weak at best, and if the drug does offer any benefit, it is slight indeed. This is precisely the conclusion of the U.S. Food and Drug Administration (FDA), and the UK’s National Institute for Health and Clinical Excellence (NICE).

 

As we reported in our story in The Atlantic, the FDA directed Roche to state on the drug’s label the following caveat:

“Tamiflu has not been proven to have a positive impact on the potential consequences (such as hospitalizations, mortality, or economic impact) of seasonal, avian, or pandemic influenza.”

An FDA spokesperson told the BMJ,

"The clinical trials... failed to demonstrate any significant difference in rates of hospitalization, complications, or mortality in patients receiving either Tamiflu or placebo.”

Yet in the wake of the H1N1 pandemic, the FDA gave temporary approval for the drug to be given to hospitalized flu patients, who are at risk of dying.

Another big unknown is just how safe - or dangerous - Tamiflu may be.

 

According to an FDA spokesperson, side effects may include potentially fatal heart problems. If the drug is going to be used to prevent death, it seems reasonable to ask whether or not its potentially deadly side effects are outweighed by potential benefits.

 

We asked the FDA whether it had required Roche to conduct an additional trial or trials looking at whether or not, on balance, the drug reduces more serious complications than it causes. This week, a spokesperson reported back that there has been no such request made to Roche.

All of which leaves open the question of why governments around the world have invested so much - on the order of $3 billion since the emergence of H1N1 last spring, according to investment bank, JP Morgan - in a drug that appears to do so little.

The answer may lie in the politics of disease.

 

Far from a commercial success when it was initially approved by the FDA in 1999, Tamiflu’s fortunes began to look up in 2003, after the SARS outbreak and the emergence of bird flu. Then Hurricane Katrina hit. In the wake of criticism over its handling of the disaster in New Orleans, the Bush Administration announced a multi-billion-dollar pandemic and bioterrorism preparedness strategy, which included stockpiling millions of doses of Tamiflu.
As the nation’s lead public health agency, the Centers for Disease Control and Prevention appears to be operating in some alternative universe, where valid science no longer matters to public policy.

 

The agency’s flu recommendations are in lockstep with Roche’s claims that the drug can be life-saving - despite the FDA’s findings and despite the lack of studies to prove such a claim. What’s more, neither the CDC nor the FDA has demanded the types of scientific studies that could definitively determine whether or not the company’s claims are true: that Tamiflu reduces the risk of serious complications and saves lives.

 

Nancy Cox, who heads the CDC’s flu program, told us earlier this year she opposes a placebo-controlled study (in which one half of patients would be given Tamiflu and the other half would be given placebo), because the drug’s benefits are already proven.

There are a couple of take-home messages here. One is pretty obvious: Tamiflu may not be doing much good for patients with the flu who take it, and it might be causing harm. The more important issue, however, involves the need for trust in science and medicine.

 

Governments, public health agencies, and international bodies such as the World Health Organization, have all based their decisions to recommend and stockpile Tamiflu on studies that had seemed independent, but had in fact been funded by the company and were authored almost entirely by Roche employees or paid academic consultants.

 

So did the Cochrane Collaboration, at least in its earlier assessments of Tamiflu. Millions of flu patients have taken the drug as a result.

That trust appears to have been misplaced, and a drug touted as beneficial on the basis of flimsy evidence has by now become so entrenched that no one appears willing to conduct the sort of study needed to prove whether or not it can, in fact, save lives.