Sometimes, what we suffer from is bigger than we think

There was a time when the makers of Tamiflu (oseltamivir) ran ads with the tagline "sometimes, what we suffer from is bigger than we think" urging folks to see their doctor for viral URIs and get treatment for the influenza.  Now, however, I think the tagline is perfect for describing the predicament clinicians, public health officials and governments are in when trying to decide what to do with neuraminidase inhibitors (oseltamivir and zanamivir) for influenza prevention and treatment. You see, what they all suffered from when trying to decide what to recommend was a missing data problem, specifically unpublished clinical trial data held back by the pharmaceutical companies (Roche and GlaxoSmithKline). This "missing data" problem was bigger, much bigger, than initially appreciated.

Today, the Cochrane Review updated the "Neuraminidase inhibitors for preventing and treating influenza in healthy adultsand children" based on full internal reports of 46 clinical trails. The key findings are that neuraminidase inhibitors reduced the duration of symptoms by 1/2-day in adults, with data uncertain in children and that there was no evidence of a reduction in hospitalisations or serious influenza complications including pneumonia in adults or children. Side-effects, such as nausea, vomiting, psychiatric events etc, were significantly more common in the oseltamivir treated groups. In prophylaxis trials, both agents reduced the risk of symptomatic influenza in individuals and in households.

Some quotes from key individuals involved with the release of this report:

Dr. David Tovey, Editor-in-Chief, Cochrane: “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."

Dr. Tom Jefferson and co-authors of the review: “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.”

Dr. Fiona Godlee, BMJ Editor: “We need the commitment of organisations 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?”

Dr. Harlan Krumholz, Yale Professor, wrote an accompanying editorial in the BMJ. In addition to describing the surprising need for more studies 15 years after the drugs were approved and listing the current and outdated public health guidelines he emphasized that "from a health system perspective, the enormous expenditures do not appear to have commensurate benefit."

UPDATE: CDC Says Stay the Course; Main reason appears to be that observational data were not included in Cochrane analysis. Of course, it is unethical to do an RCT in a pandemic, so much of the data required for decision making around pandemic preparedness wouldn't be from RCTs.

Additional References:
1) Heneghan et al. Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments BMJ 2014

2) Jefferson et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014

Epidemiologic activists

There's an excellent article in this morning's New York Times on the quest by the Cochrane group to determine the efficacy of Tamiflu, which is part of a bigger story on how pharmaceutical companies selectively release data regarding their products. It demonstrates how epidemiology can involve more than just data analysis and how political activism is sometimes required to find the data to answer basic questions.

Photo: Dr. Tom Jefferson by Chris Warde-Jones for the New York Times.

In the news

Just about every day, I take a look at what's appearing in the mainstream media so that readers of this blog can link to the latest, hottest happenings in the world of infectious diseases and infection prevention. Today's foray yielded a treasure trove:

• First it was Christmas decorations. Then aquariums. Now British hospitals are banning flowers on wards in the name of infection prevention. I suggest they next ban food, water, and air, since none of those are sterile either.
• Two of four patients who received organs from a patient who died at the University of Mississippi Medical Center last month have been diagnosed with infections due to Balamuthia mandrillaris, a free-living amoeba that can cause encephalitis. Both patients are critically ill. Infections with these organisms are rare, and these are the first to be transmitted via transplanted organs.
• Dr. Sidney Wolfe, the well known patient advocate at Public Citizen, has added Tamiflu to his list of worst pills. The title of the press release says it all--"Tamiflu? More like Scamiflu."
• In Scotland, three injection drug users have developed cutaneous anthrax, one of whom has died of the infection.
• Lastly, if you are planning on having plastic surgery anytime soon in Connecticut, be careful! A plastic surgeon there has been cited because inspectors found mouse poop on her surgical instruments. I didn't make this up, really! See the link here.

"The Truth about Tamiflu"

A few months ago, Dan and I both blogged (here and here) about an interesting article in The Atlantic that questioned the effectiveness of the influenza vaccine. Now, the same investigative journalists, Shannon Brownlee and Jeanne Lenzer, have a new piece, "The Truth about Tamiflu," in The Atlantic. They examine the controversy about the effectiveness of tamiflu that I blogged about yesterday. Like their previous article, this one is well-written and definitely interesting.

Tami-fly-by-night?

This week's BMJ contains an updated Cochrane Review on neuraminidase inhibitors for treating and preventing influenza. The journal issue also contains several other related articles, primarily focusing on the controversial aspects behind the review. The previous Cochrane Review used a meta-analysis that relied heavily on unpublished data. For the update, the Cochrane reviewers tried to obtain the primary data from Roche, but were unable to do so, and the study in question was eliminated from the new review. The review concludes that the drugs are modestly effective in the treatment of influenza and not effective at preventing influenza-like illness since only a small fraction of ILI cases are caused by influenza. In a separate publication in the same issue, Peter Doshi, one of the authors of the Cochrane review, states: "We are no longer sure that oseltamivir offers a therapeutic and public health policy advantage over cheap, over the counter drugs such as aspirin."  


So, how much money has been spent on a drug of questionable effectiveness?

More on Tamiflu at summer camps

This morning's New York Times has an article on the issue of prophylactic Tamiflu at summer camps, which Dan blogged about two weeks ago. CDC says the practice is wrong because it wastes a limited resource and may lead to antiviral resistance. On the other hand, Dr. Marc Siegel, an internist with a child in summer camp disagrees. He argues that his son at camp, with a bunkmate who had influenza, could bring the virus home and infect his brother who has asthma. Given that there appears to be no shortage of Tamiflu at the the present time, I side with Dr. Siegel, and hope that many more kids enjoy a flu-free camp experience.

Beautiful Camp Inna Fluenza, on Lake Tamiflu

Thanks to Kathy in the comments section for pointing me to this interesting article in Slate, describing an H1N1 outbreak at a Maine summer camp. I understand the desire to hold oseltamivir in reserve for those at highest risk, but I’m still surprised that the Maine Department of Public Health was initially reluctant to use prophylaxis during a clear H1N1 outbreak at a large summer camp. Protecting several hundred youngsters who will soon be boarding buses and planes back to their home communities seems like a smart public health move, regardless of the likelihood that any individual camper will suffer an adverse outcome from H1N1. This issue is picking up speed, with outbreaks at other camps hitting the news as well. I’m also copying, below, a query from a pediatric ID physician in New Jersey, from this morning’s Emerging Infections Network listserve:

"I have received several calls from camp directors or physicians because of influenza in sleepaway summer camps. They are already working in accordance with ACA and state guidelines but as a result, many children are being isolated for 7 days or are being sent home regardless of duration and severity of symptoms without any testing as the current recommendations recommend this regardless of flu test result. In one camp, the sicker children were tested and tested positive for fluA. Now, any child who presents with a single isolated temp above 100 and any other symptom is being removed for 7 days. However, no one is particularly ill and many are well within a day.

For the children who test positive for fluA, the answer is fairly straightforward. However, summer colds and strep do happen at camps and many children may be isolated who either do not need it or who have something else that does not necessitate this (eg, strep after abx). I think it is reasonable for kids with sore throat and fever to be tested for strep--if positive, treat, etc. It may also be reasonable to test those with fever and cough for flu (they are picking it up on their rapid kit with some success)--if positive, follow the guidelines as they currently exist. The quandary is what to do with a child who is negative and is well within two days and whether or not they may return to their bunk and activities.

Obviously the camps will comply with local health authorities. Any other thoughts?"

So what do you think? If you were a summer camp director, or camp nurse, or local public health official, how would you manage H1N1 risk at camp?

Blackmarket Tamiflu?

Like many hospitals, we have restricted use of oseltamivir to patients meeting predetermined criteria. However, I heard today that the drug could be purchased on eBay. I went to investigate the rumors and found that as of this evening there was no tamiflu for auction on eBay. There were, however, 2 Tamiflu pens available for immediate purchase at $9.99. A little overpriced, don't you think?