A new systematic review of clinical studies of the oral anti-influenza drug oseltamivir that included a substantial amount of clinical data that were not part of previously published assessments showed that significant questions exist about oseltamivir’s role in treating and preventing influenza and in pandemic preparedness.
"Our results show that oseltamivir reduces the proportion of participants with symptomatic influenza when used for prophylaxis and has modest symptomatic effects when used for treatment, but it also causes nausea and vomiting and increases the risk of headache and renal and psychiatric syndromes," Tom Jefferson, Ph.D., wrote in an article published online on April 9 (BMJ 2014;348:g2545 doi:10.1136/bmj.g2545).
"We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the [World Health Organization] list of essential drugs, and its use in clinical practice as an anti-influenza drug," concluded Dr. Jefferson, an epidemiologist with the Cochrane Library and head of the Italian Health Technology Assessment program in Rome, and his coauthors. "The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling," they wrote.
A second, simultaneously-published study by the same Cochrane-based group using previously unavailable clinical-study data for zanamivir, an inhaled anti-influenza drug, found that, while zanamivir treatment safely reduced by half a day the time to improvement in adults with symptomatic influenza, it had no effect on reducing the risk of complications of influenza, particularly pneumonia, or the risk for hospitalization or death, nor did it show any efficacy for reducing asymptomatic influenza and the subsequent risk for transmission (BMJ 2014;348:g2547 doi:10.1136/bmj.g2547).
The newly available data used by the Cochrane researchers in both reviews came from the manufacturers of the two drugs, Roche in the case of oseltamivir (Tamiflu) and GlaxoSmithKline in the case of zanamivir (Relenza). "Owing to the risk of reporting bias there are legitimate reasons to doubt the stated benefits of oseltamivir and the results of previous Cochrane reviews of neuraminidase inhibitors in adults and children," wrote Dr. Jefferson and his associates in the oseltamivir report.
"To tackle these problems, we have conducted a 4-year campaign to obtain full study reports of the oseltamivir trial program" as well as a parallel campaign that yielded full study reports for zanamivir. The 4-year campaign noted in the review involved an unusual collaboration between Dr. Jefferson and his Cochrane associates and editors at BMJ to put ongoing pressure on Roche and GlaxoSmithKline to promise and then follow through on delivering the full clinical reports from the drugs’ studies, data that finally reached the Cochrane researchers in late 2013.
"For the first time, a Cochrane review [on neuraminidase inhibitors] is based on all relevant full clinical study reports of a family of drugs, integrated by regulatory comments," the authors wrote. "We are pretty confident that this is the closest you’ll get to an unbiased data set," Dr. Jefferson added in an interview.
Despite the unprecedented completeness of the data behind the two reports and the questions they raise about the two drugs, Dr. Jefferson expressed skepticism that public health policy in the United States or United Kingdom will change as a result of the publications.
"I don’t think the people who made the decision to stockpile these drugs for influenza can make an objective decision with any new evidence. [Oseltamivir] was stockpiled but the evidence of its toxicity wasn’t ‘discovered’ by us. It’s been known since the 1990s. I’m skeptical [there will be change now] because the whole system needs to be overhauled. Individual physicians are very loath to prescribe these drugs. But for public health decisions I’m not holding my breath," Dr. Jefferson said.
In reply to a request for comment on the new reports, Gregory Härtl, a spokesperson for the WHO in Geneva, made this statement: "WHO has not seen the paper so cannot comment on specifics. We welcome a new and rigorous analysis of available data and look forward to consideration of its findings after it appears. WHO is committed to an evidence-based approach to determining the best advice for patient care."
Jason McDonald, a spokesperson for the Centers for Disease Control and Prevention in Atlanta made this statement: "CDC supports efforts to make public previously unpublished data from clinical trials. CDC and its advisory committee on immunization practices review all relevant scientific literature when making policy decisions about public health. Clinical trials are just one component of the overall body of scientific evidence that CDC and ACIP [Advisory Committee on Immunization Practices] review when making clinical recommendations on antiviral drugs. Observational trials are another such component, and CDC and ACIP have reviewed a considerable and ever growing number of such studies that show the benefits of antiviral medications in not only reducing and shortening symptoms of disease but also preventing hospitalizations and deaths, including in high risk children and adults. While there are limitations and possible biases that must be considered and controlled in such studies, these studies are easier to conduct due to ethical considerations and more of them are available.