Studies Cast Doubt on Need to Stockpile Influenza Drugs

Larry Hand

April 10, 2014

Results of 2 new systematic reviews of neuraminidase inhibitors oseltamivir (Tamiflu, Roche) and zanamivir (Relenza, GlaxoSmithKline) cast doubt on whether governments should stockpile the drugs to slow the spread of seasonal or pandemic influenza, according to articles published online April 9 in the BMJ.

The BMJ articles are based on an updated Cochrane systematic review, published simultaneously.

For the first time, the reviewers had access to internal documents provided by the drug manufacturers rather than just published peer-reviewed studies. Such internal reports are submitted to the regulatory agencies for consideration during the drug-approval process but are not normally available to the public. The internal documents covered clinical trials that involved more than 24,000 participants.

"We now have the most robust, comprehensive review on 'neuraminidase inhibitors' that exists," David Tovey, MD, editor in chief at the Cochrane Library, said in a news release. "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. This shows the importance of ensuring that trial data are transparent and accessible."

Meanwhile, the United States has spent more than $1.3 billion to stockpile antiviral drugs, according to a government document. The United Kingdom has spent about £424 million for stockpiling antivirals, according to a British Parliament publication.

Oseltamivir Study

For the oseltamivir study, Tom Jefferson, MD, from the Cochrane Acute Respiratory Infections Group, Rome, Italy, and colleagues obtained clinical study reports from 84 clinical trials, 20 of which were included in their final analysis.

They found that oseltamivir reduced the time to first symptom alleviation in adults by 16.7 hours (95% confidence interval [CI], 8.4 - 25.1 hours; P < .001) in treatment trials. In healthy children, the benefit was a mean difference of 29 hours (95% CI, 12 - 47 hours; P = .001), but the researchers found no difference in children with asthma. In addition, there was no significant difference between oseltamivir and placebo in rates of hospital admissions in the treatment trials in adults (risk difference [RD], 0.15%; 95% CI, –0.91% to 0.78%; P = .84).

However, in treatment trials, oseltamivir increased the risk for nausea (RD, 3.66%; 95% CI, 0.90% - 7.39%; number needed to treat to harm (NNTH), 28; 95% CI, 14 - 112) and vomiting (RD, 4.56%; 95% CI, 2.39% - 7.58%; NNTH, 22; 95% CI, 14 - 42) in adults and for vomiting in children (RD, 5.34%; 95% CI, 1.75% - 10.29%; NNTH, 19; 95% CI, 10 - 57).

In prophylaxis trials, the researchers found that oseltamivir reduced the risk for symptomatic influenza in participants and households but had no effect on asymptomatic influenza.

They also found no evidence of a reduction in viral transmission with oseltamivir. Such an interruption in spread was a key part of the rationale for the World Health Organization (WHO) to recommend use of the drug during a pandemic. Moreover, the current reviewers note that the trial on which that decision was based had design flaws.

Oseltamivir increased the risk for psychiatric adverse events during prophylaxis trials in general, the researchers write, and in 2 pivotal treatment trials they observed a dose-response effect. Oseltamivir also increased the risk for headaches and nausea.

"We believe these findings provide reason to question the stockpiling of oseltamivir, its inclusion on the WHO list of essential drugs, and its use in clinical practice as an anti-influenza drug," the reviewers conclude.

Zanamivir Study

For the zanamivir study, Carl J. Heneghan, MD, from the Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom, and colleagues included 26 clinical trial reports in their final analysis.

They found that in treatment trials zanamivir reduced the time to first symptom alleviation in adults by 0.6 day (95% CI, 0.39 - 0.81 day; P = .001), equating to a reduction of 14.4 hours. However, they note that symptom relief could partially be related to other symptom-relief drugs also taken during trials.

In prophylaxis trials, zanamivir significantly reduced the risk for symptomatic influenza in individuals (relative risk, 0.39; 95% CI, 0.22 - 0.70) but did not significantly reduce the risk for asymptomatic influenza in individuals (RD, 0.14%; 95% CI, –1.10% to 1.10%) or in households (RD, 1.32%; 95% CI, –2.20% to 3.84%).

The researchers found no significant effect for zanamivir on pneumonia in adults and no significant effect of zanamivir in lessening the risk for any serious complications.

"We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of admission to hospital or death," the researchers write.

Transparency Essential for Health Policy

"With the comprehensive new reviews based on all the data, the perspective has changed substantially," writes Harlan M. Krumholz, MD, professor of medicine at Yale University School of Medicine, New Haven, Connecticut, in 1 of 2 editorials published alongside the systematic reviews.

Yet, even with all the new data available, he notes, "many questions linger, which is remarkable given that the drugs have been approved for 15 years."

He continues, "Of primary importance for decision makers is that now, with all of the data available for others to evaluate, the knowns and unknowns can be laid out clearly, revealing the weakness of the evidentiary support for these products and what exactly we need to learn for the future."

In the second editorial, Elizabeth Loder, MD, MPH, chief of the Division of Headache and Pain at Brigham and Women's Hospital in Boston, Massachusetts, and clinical epidemiology editor for the BMJ, Dr. Tovey, the Cochrane editor in chief; and Fiona Godlee, MD, editor in chief of the BMJ, address the broader issue of drug evaluation and transparency.

They conclude, "The Cochrane reviewers' exceptional efforts have achieved what should have been a matter of routine: the independent scrutiny of deindentified clinical trial data. They have shown with greater clarity than ever that the current system is broken. There are substantial battles still to fight before we have a system of drug evaluation and regulation that truly serves patients and the public interest."

A Balancing Act Remains

"I do agree that it is absolutely important to have transparency and to be honest and open about all of the data. All studies should be conducted with transparency," Gail Reid, MD, assistant professor of infectious diseases at Loyola University Stritch School of Medicine in Maywood, Illinois, told Medscape Medical News.  

She added, however, "One concern I have about the study is that neuraminidase inhibitors might be discounted completely for influenza.  We have had subsequent studies [not pharmaceutically sponsored] that have shown some benefit with limited side effects, so I would not discount these drugs for influenza despite these recent papers."

Andrew Bonwit, MD, also assistant professor of infectious diseases at Loyola Stritch and a pediatric infectious disease clinician, told Medscape Medical News that the reviews make interesting and important knowledge contributions because of the limited availability of information on how well oseltamivir and zanamivir work to change the course of illness.

However, he added, "The treatments have at least some usefulness in light of the lack of adequate vaccine coverage, possibly more of an ability to prevent disease than to shorten" time to relief.

The big question, he said, is, "Should we spend so much money stockpiling them? I would say it should still be part of what we do. Some kind of ability to ameliorate an epidemic is better than no ability to ameliorate it. Maybe we should be very critical in assessing how much of it we stockpile. The bigger effort should go toward wider coverage of the population with vaccine and improvements in the efficacy of vaccines."

This research was funded by the United Kingdom National Institute for Health Research (NIHR). Four authors have reported that they are co-recipients of the NIHR grant to carry out this review; 2 authors have reported receiving royalties from published books; Dr. Jefferson has reported acting as an expert witness in a litigation case related to oseltamivir phosphate and in a labor case on influenza vaccines in healthcare workers in Canada and acting as consultant for 3 pharmaceutical companies and for IMS Health; Dr. Heneghan has reported receiving payment for running educational courses at the University of Oxford and University of Oxford ISIS consulting services for external teaching and training. None of the other authors have disclosed any relevant financial relationships. Dr. Krumholz has reported receiving, through his institution, grants from Medtronic and Johnson & Johnson and serving as chair of a cardiac scientific advisory board for United Health. Dr. Godlee has reported that she and the BMJ have been "closely involved from the outset in the campaign for access to clinical trial data on oseltamivir." Dr. Reid reports that she is participating in a study subsidized by Hoffmann-LaRoche measuring duration of viral shedding in transplant recipients with influenza. Dr. Bonwit has disclosed no relevant financial relationships.

BMJ. Published online April 9, 2014. Oseltamivir review Zanamivir review Krumholz editorial Loder editorial

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