- Harlan M Krumholz, Harold H Hines Jr professor of medicine1,
- Cynthia A Jackevicius, associate professor, pharmacy practice2,
- Joseph S Ross, assistant professor1
- 1Yale University School of Medicine, New Haven, CT 06510, USA
- 2College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
In the midst of a worse than average influenza season, clinicians are increasingly prescribing antiviral agents, especially oseltamivir (Tamiflu). Oseltamivir, an oral neuraminidase inhibitor, was first approved for use by the US Food and Drug Administration in 1999. It is indicated “for the treatment of acute, uncomplicated illness due to influenza infection in patients 2 weeks of age and older who have been symptomatic for no more than two days,” and, “for the prophylaxis of influenza in patients 1 year and older,” with similar indications worldwide. Despite these broad indications, some government agencies promote even wider use. For instance, the website of the US Department of Health and Human Services states that oseltamivir may prevent serious complications of flu, and the US Centers for Disease Control and Prevention’s website states that early antiviral treatment may reduce the risk of complications of flu and death.1 2 Business analysts expect rising sales of oseltamivir to reach $750m (£474m; €562m) this year alone.3
Despite such enthusiasm, some basic questions remain unanswered, including the most crucial: what do we really know about oseltamivir’s effectiveness and who benefits from treatment? With the huge number of people affected and such remarkable sales, the evidence to support the use of oseltamivir should be strong. Yet despite the 14 successive flu seasons since the FDA first approved the drug, definitive trials of oseltamivir across diverse populations for a variety of important outcomes are lacking. More importantly, results of many of the trials that have been conducted remain unpublished or only partially published (www.bmj.com/about-bmj/article-clusters/tamiflu).
The Cochrane Collaboration’s most recent systematic review of neuraminidase inhibitors, including oseltamivir, for healthy adults and children states, “due to limitation in the design, conduct, and reporting of the trial programme, the data available to us lacked sufficient detail to credibly assess a possible effect of oseltamivir on complications and viral transmission.” It concluded, “we found a high risk of publication and reporting biases in the trial programme of oseltamivir.”4 The review was based on 25 studies, 15 of which were on oseltamivir. Twenty other identified studies could not be included because of insufficient information or unresolved discrepancies in the data. Crucially, in an effort to include all identified studies, the Cochrane investigators requested full clinical study reports from Roche, the funder of all but one of the studies. But data from these studies were not provided, which prevented the inclusion of some studies in the systematic review and also prohibited scrutiny of the research by the scientific community.
Nevertheless, the Cochrane investigators obtained information directly from the European Medicines Agency, and a full examination of the available data failed to identify a benefit of oseltamivir on risk of hospital admission. There was still insufficient evidence to assess its effect on risk of flu complications.
So does oseltamivir work at all? The Cochrane investigators found that the available data showed that, when used early, oseltamivir shortened the duration of flu symptoms by 21 hours, from an average of nearly seven days to six. Unfortunately, they could not assess whether symptoms relapsed. Moreover, these findings were based on the results of only five of the 15 available studies (those that reported this specific outcome), of which only two were published. For all the available studies, unpublished clinical study reports were used. In addition, the investigators identified an additional three trials that reported this outcome that could not be included because data were not available.
The lack of benefit in reducing hospital admissions is particularly striking given that oseltamivir is listed as an essential drug by the World Health Organization, many government agencies recommend it, many clinicians prescribe it, and many patients seek it explicitly in the hope of avoiding complications once they have flu-like symptoms.
What is the way forward for patients and clinicians? Firstly, despite government claims, we should acknowledge the uncertainty surrounding oseltamivir’s effectiveness and the gaps in publicly available evidence. On the basis of the available data, at best the drug shortens symptoms by about a day when used within the first two days of symptoms, but it has no effect on hospital admissions. In addition, trial data from which to draw conclusions about complications and transmission of flu are lacking. However, any effect of the drug on shortening symptoms is based on only a proportion of the identified studies; to trust the result, we must assume that data from all studies would concur and support these conclusions.
The story of oseltamivir is an indictment of our current research enterprise. A blockbuster drug has been allowed to dominate a market in the absence of ample and rigorous evidence of effectiveness. A drug that is used so widely at great cost should require a commensurate evidence base.5 We need non-industry sponsored comparative effectiveness trials to answer the questions of who benefits from the drug and by how much.
Independent trials of oseltamivir should be easy to conduct given the large number of eligible patients and short time needed to ascertain clinically meaningful outcomes. Some of the uncertainty about oseltamivir and other neuraminidase inhibitors could be mitigated immediately if the manufacturers made all related clinical trial data available for independent analysis. The medical profession and the public must insist that—for the privilege of selling any product, particularly one that generates substantial annual revenue and has marked public health implications—all available data relevant to risks and benefits are disclosed so that independent assessments can be performed.
Without stronger evidence generation and assurance that all previously collected data and findings will be disseminated, we are left guessing about the true effectiveness of this drug. How many more flu seasons will pass before we know the answers?
Cite this as: BMJ 2013;346:f547
Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: HMK and JSR receive support from Medtronic via a research grant through Yale University; HMK is supported by grant U01 HL105270-03 (Center for Cardiovascular Outcomes Research at Yale University) from the National Heart, Lung, and Blood Institute in Bethesda, MD, and chairs a scientific advisory board for United Health; JSR is supported by the National Institute on Aging (K08 AG032886) in Bethesda, MD, and by the American Federation for Aging Research in New York, NY, through the Paul B Beeson Career Development Award Program and is a member of a scientific advisory board for FAIR Health in New York, New York.
Provenance and peer review: Commissioned; not externally peer reviewed.