Thursday, April 10

The increasingly strange story of Tamiflu and Relenza anti-viral drugs

"The patent for oseltamivir [generic name of Tamiflu] is held by Gilead Sciences and is valid at least until 2016. Gilead licensed the exclusive rights to Roche in 1996. ... Gilead is politically well connected: Donald Rumsfeld served as chairman from 1997 until he became U.S. Secretary of Defense in 2001; former Secretary of State George Shultz and the wife of former California Governor Pete Wilson serve on the board.
"In November 2005, U.S. President George W. Bush requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Rumsfeld recused himself from all government decisions regarding the drug."
-- From Wikipedia's article on oseltamivir

I suggest you study Wikipedia's entire article before you read the following news report, Researchers raise questions about flu drugs.  The new study is by no means the first time research findings have raised questions about the drugs. And while I don't recall whether Wikipedia mentions this, Tamiflu was supposed to be a resort for people with already compromised immune systems who manifested flu symptoms. That was before Swine Flu, when governments began dispensing Tamiflu from their stockpiles as if it was Halloween candy.  From then on the drug was heavily marketed to the general public for any type of flu. 

The trick that went along with the treat was that the Swine Flu virus had a lot of fun with Tamiflu when the drug got into wide use.  See this March 2014 article for information on that angle, and there are many other articles on the subject of anti-viral drugs and viral mutations.)
If Tamiflu or Relenza were a magic bullet, you could make out an argument that in a crisis, with hundreds of millions of human lives at stake, you have to take your chances with the possibility of an extremely deadly mutation arising from the virus's battles with the antivirals.
But Tamiflu is not a magic bullet and neither is Relenza.  So I think physicians and public health officials might want to do a little weighing motion with their hands: Possibility of Doomsday Virus vs. Recommending the Patient Gargle With Salt Water.

Researchers in this area of medical science are trying to find a way to thread the camel by screwing around with genomes, as you can see from the March 2014 article.  Here I'm reminded of I am Legend -- the movie; I didn't read the book. Although the story got the Hollywood focus-grouped treatment it was at root a parable about human overreach.

One thing I would like to know about Tamiflu: Just how was it that the drug developer got the idea to distill the main ingredient in a cooking spice, star anise, to create the key ingredient in the drug?  Did the idea come in a dream?  Through the dartboard method of drug development?  From gazing into a crystal ball, perhaps?  Or was it by reading books on Chinese and Indian traditional medicine? 

The bolded emphasis in this news report is mine:
Researchers raise questions about flu drugs

Michelle Healy, USA TODAY 7:03 p.m. EDT April 9, 2014

A new review is questioning the effectiveness of two key drugs enlisted in the fight against influenza and in turn the investments by governments to stockpile the drugs in the event of a global flu outbreak.
The antiviral drugs Tamiflu (oseltamivir) and Relenza (zanamivir ) are commonly used to treat influenza in healthy adults and children.

In the case of Tamiflu, the drug does shorten symptoms of influenza by about half a day — as the manufacturer suggests — but there is insufficient evidence to support claims that it reduces hospital admissions or serious complications, such as confirmed pneumonia or bronchitis, says the review published today by The Cochrane Collaboration, a non-profit, international health-care research network, and the British medical journal BMJ.

The review also cites evidence from treatment trials (when the drug was given for about five days) that Tamiflu increased the risk of nausea and vomiting in adults by around 4% and in children by around 5%.
And evidence from prophylaxis or prevention trials (when the drug was given for about six weeks) showed Tamiflu use was related to increased risks of headaches, psychiatric disturbances, especially depression and confusion, and renal problems.

The review of studies related to the nasal spray Relenza found fewer adverse effects compared with Tamiflu, but also showed no effectiveness against flu complications or reducing hospitalizations.

Although Relenza likewise reduced symptoms by about half a day, the reviewers report "that it may be no better than other symptom relief medications," such as drinking clear liquids, gargling with warm salt water, and using saline nasal drops, over-the-counter decongestants, and pain relievers such as acetaminophen and ibuprofen.

In a statement, Relenza-maker GlaxoSmithKline says, "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."

Tamiflu-maker Genentech, a division of Roche, also challenged the review's conclusions, noting that the researchers focused on only 20 out of 77 clinical trials, "all made available to them," and excluded "real-world data" from non-Roche-sponsored observational trials.

In some cases, the reviewers also failed to analyze the appropriate statistical information, which "doesn't give you an accurate representation of what the true effect of the medicine is," says Barry Clinch, principal clinical scientist with Roche.

Peter Doshi, an assistant professor of pharmaceutical health services research at the University of Maryland School of Pharmacy and a co-author of the Cochrane review, says he's not interested in "health scares. What we've found here are statistically significant increases."

"Do I know absolutely for certain, without a shadow of a doubt, that Tamiflu is responsible for these (negative effects), based on the trial methodology? No. But what I'm seeing here are clear reasons to be concerned about and to look into it further," he says.

Claims about the effectiveness of the antiviral drugs were a key factor in decisions made by governments around the world to stockpile the drugs in case of a global flu outbreak and was widely used during the 2009 H1N1/swine flu pandemic, says Fiona Godlee, editor-in-chief, BMJ.

Since that pandemic, Cochrane investigators, commissioned by the United Kingdom government, have attempted "to get to a sound evidence base as to whether this drug was effective and safe," says Godlee.
The new report cites a U.S. Government Accounting Office (GAO) document stating that the U.S. has spent more than $1.3 billion buying a strategic reserve of antivirals. The British government has spent almost £424 million or $710,030,400 for a stockpile of about 40 million doses, according to documents.

Unlike the case in many countries, FDA-approved labeling for Tamiflu says that the drug "has not been shown" to prevent serious bacterial complications like those associated with pneumonia and other upper respiratory infections, a fact that "contradicts the assumptions that were made when stockpiling occurred," Doshi says.

In 2012, after reviewing an earlier Cochrane review that raised similar questions about the value of the antiviral medications for the prevention and treatment of influenza, the Centers for Disease Control and Prevention did not change its recommendation on the use of the antiviral drugs, calling them "an important adjunct in the prevention and treatment of influenza."

CDC's response this week was similar. "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."


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