Blog | Monday, May 5, 2014

'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 upper respiratory infections and get treatment for 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You see, what they all suffered from when trying to decide what to recommend was a missing data problem, specifically unpublished clinical trial data held back by the pharmaceutical companies (Roche and GlaxoSmithKline).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 adults and children” based on full internal reports of 46 clinical trials. The key findings are that neuraminidase inhibitors reduced the duration of symptoms by a half-day in adults, with data uncertain in children and that there was no evidence of a reduction in hospitalizations 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 hospitalizations 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 organizations 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 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 a randomized, controlled trial in a pandemic, so much of the data required for decision making around pandemic preparedness wouldn’t be from such trials.

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

Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands). This post originally appeared at the blog Controversies in Hospital Infection Prevention.