Latest Roche-Sponsored Tamiflu Review Enters the Fray

Janis C. Kelly

February 10, 2015

A meta-analysis of individual patient data from nine randomized controlled trials that compared oseltamivir (Tamiflu, Roche) with placebo found a modest reduction in symptom duration and respiratory complications. But critics caution that those benefits have to be weighed against an increase in adverse effects and point out that the new analysis was funded by Roche through an outside group.

Although the Centers for Disease Control and Prevention currently recommends prescribing antiviral agents to high-risk individuals with suspected influenza infections, the effectiveness of oseltamivir remains a matter of debate.

In 2014, Tom Jefferson, MD, and researchers from the Cochrane Collaboration Acute Respiratory Infections Group reported a systematic review of 23 randomized, controlled trials that included 9623 participants exposed to naturally occurring influenza. The Cochrane reviewers found that oseltamivir shortened the time to relief of influenza symptoms in adults by about 1 day, but had no effect on risk for hospitalization or pneumonia and did not reduce influenza transmission.

In the current article, published online January 29 in the Lancet, Joanna Dobson, MSc, lecturer on medical statistics, London School of Hygiene & Tropical Medicine, United Kingdom, and colleagues ask the same questions about effectiveness and adverse outcomes, but they analyzed patient-level data from "all published and unpublished Roche-sponsored" randomized controlled trials. The trials included 4328 patients who received either oseltamivir or placebo for treatment of seasonal influenza. Their primary outcome was the time to alleviation of all influenza symptoms, and they analyzed both the entire intention-to-treat (ITT) population and the subset of ITT patients with proven influenza infection (ITT-infected group).

1 Fewer Day of Influenza Symptoms, Slightly More Nausea, Vomiting

Similar to the Cochrane review, Dobson's team found that oseltamivir reduced median symptom duration by 25.2 hours (95% confidence interval [CI], 36.2 - 16.0 hours) in the ITT-infected group and by 17.8 hours (95% CI, 27.1 - 9.3 hours) in the entire ITT population.

In the infected-ITT subgroup analyses, they found that oseltamivir also reduced the risk for lower respiratory tract complications requiring antibiotics more than 48 hours after randomization (4.9% oseltamivir vs 8.7% placebo; risk difference [RD], −3.8%; 95% CI, −5.0% to −2.2%) and the rate of hospital admission for any cause (0.6% oseltamivir vs 1.7% placebo; RD, −1.1%; 95% CI, −1.4% to −0.3%).

Dobson and colleagues also report that oseltamivir increased rates of nausea (9.9% oseltamivir vs 6.2% placebo; RD, 3.7%; 95% CI, 1.8% - 6.1%) and vomiting (8.0% oseltamivir vs 3.3% placebo; RD, 4.7%; 95% CI, 2.7% - 7.3%) in the safety population, which was defined as all patients who received one or more doses of study drug or placebo.

"The balance of benefits and harms becomes less favourable if more non-infected participants are treated with oseltamivir," they write. "Treatment strategies need to avoid this — eg, through availability of rapid diagnostic testing. This highlights the value of additionally reporting results for the [ITT] infected population."

In an accompanying comment, Heath Kelly, MBBS, from the Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia, and Benjamin J. Cowling, PhD, from the World Health Organization Collaborating Centre for Infectious Disease Epidemiology and Control, University of Hong Kong, China, write that oseltamivir might reduce symptom duration, lower respiratory tract infection requiring antibiotics, and hospital admission for any cause, but only in influenza virus–infected patients.

Therefore, Dr Kelly and Dr Cowling only recommend presumptive use of the drug in pandemic settings where there is a high probability that influenza-like illness is caused by influenza virus infection. In contrast, under more typical conditions, they recommend the drug only be used if influenza infection is confirmed.

Roche Funding Becomes an Issue

Dr Kelly and Dr Cowling also note that Dobson's group is not entirely independent of Roche, which manufactures oseltamivir. "The re-analysis was funded by an unrestricted grant from Roche but was done by an independent research group [the Multi-Party Group for Advice on Science, MUGAS], thus seeking to overcome the suggested bias associated with industry-funded studies."

When asked directly about any ties to Roche, Dobson told Medscape Medical News that she and coauthor Stuart Pocock, PhD, professor of medical statistics, London School of Hygiene & Tropical Medicine, United Kingdom, "are the independent statistical centre for this study. As stated in our paper, MUGAS and Roche had no role in the analysis, interpretation, or reporting of this study."

Another coauthor, Arnold S. Monto, MD, professor of epidemiology, University of Michigan School of Public Health, Ann Arbor, told Medscape Medical News that MUGAS was not formed by Roche but by the European Scientific Working Group on Influenza, which met in Brussels, Belgium, in June 2013, after which the study authors were asked to conduct the analysis. "This was done independent of Roche or MUGAS, with firewalls erected," he said.

However, according to the 2013 Roche press release announcing the formation of MUGAS, "a MUlti-party Group for Advice on Science (MUGAS) will be set up by four renowned scientists in the field of influenza to look at data on Tamiflu, identify any unanswered questions and agree on a statistical analysis plan. Following an agreement, Roche will provide access to all requested Tamiflu clinical trial data for the analyses.

"The four scientists will invite independent experts and third parties to their meeting, which is scheduled to take place in June. The four scientists are Prof Albert Osterhaus, Erasmus Medical Centre Rotterdam; Prof Menno De Jong, Academic Medical Centre Amsterdam; Prof Arnold Monto, University of Michigan and Prof Richard Whitley, University of Alabama." Dr Whitley is also a coauthor on the current paper.

In fact, an examination of the European Scientific Working Group on Influenza website includes corporate videos from both Roche and GlaxoSmithKline, which makes the neuraminidase inhibitor zanamivir (Relenza). And the European Scientific Working Group on Influenza and MUGAS websites list the same contact, which suggests the entities do have at least some overlap in structure.

Dobson and colleagues acknowledge that Roche funding of the study was channelled through MUGAS and that MUGAS partly funded Dobson's salary during this project. Coauthor Richard J. Whitley, MD, is also on the board of the directors of Gilead, which holds the patent for Tamiflu and, jointly with Roche, oversees manufacturing, commercialization, and pandemic planning for the drug.

Are Researchers Less Objective Than They Think?

Previous studies suggest that such industry ties can influence the outcome of systematic analyses. For example, in an analysis of financial conflicts of interest and conclusions in systematic reviews of neuroaminidase inhibitors published in October 2014, Adam G. Dunn, PhD, senior lecturer at the Center for Health Informatics, University of New South Wales, Sydney, Australia, and colleagues found that reviewers with financial conflicts of interest were more likely to present evidence "in a favorable manner" and to recommend the drugs evaluated compared with reviewers without financial conflicts.

When asked by Medscape Medical News about the newly published study by Dobson and colleagues, Dr Dunn said, "My personal view is that reviews should always be considered in the context of who wrote them, and that while financial conflicts of interest do not always lead to biases, there are well-established associations between financial conflicts of interest and conclusions that are biased in ways that favor pharmaceutical companies. Contrary to the accompanying editorial, I would not consider the MUGAS foundation group to be independent of Roche, given the nature of the authors' financial ties to the company."

Dr Dunn added that some of the results of the new oseltamivir review appear to be in direct conflict with those of the 2014 Cochrane systematic review. These conflicts include conclusions about reducing hospitalizations and complications, as well as adverse events such as headaches and psychiatric events.

"In each case, the Dobson et al review favors [oseltamivir]," Dr Dunn said. "It is also consistent with our finding that the processes underpinning the construction of systematic reviews answering the same clinical question can be affected by undetected biases (unintended or deliberate) that lead to different conclusions."

And Maybe Not Systematic?

Chris Del Mar, MB BChir, MD, head of the Cochrane Collaboration Acute Respiratory Infections Group and professor of public health, Centre for Research in Evidence-Based Practice, Bond University Gold Coast, Queensland, Australia, told Medscape Medical News that the Dobson article is a welcome addition to the debate about the use of oseltamivir but expressed a number of concerns about the article's methodology and conclusions.

Dr Del Mar said that although the analysis of patient-level data allows a more precise estimate of effects with narrower confidence levels and makes possible subgroup analyses, there are concerns about the researchers' recommendations.

"Even if we accept these findings [of a 63% reduction in hospitalization in the ITT-infected population], the crucial finding is that only three hospitalizations will be avoided with 1000 courses of oseltamivir, assuming epidemic rates of ~30% of possible cases actually being infected with influenza (rather than influenza like–illness — meaning illness caused by another virus)," Dr Del Mar said.

Dr Del Mar also pointed out that Dobson and colleagues used a subgroup of the trials in the Cochrane review (no children and no prophylactic trials), plus one additional study. In addition, he argued that it was not really a systematic review because it did not include assessment of the quality (risk for bias) from individual trials; was not registered, as is now the expected norm after the PRISMA statement; and included no a priori declaration of the methods.

Dr Del Mar was also bothered by the authors' use of antibiotic prescription as a proxy for bacterial infection. "This is very dangerous in this situation, as we know that antibiotics are overused for 'acute bronchitis' in a haphazard manner by clinicians," he said.

Elderly, Bronchitis Also Problematic

Carl Heneghan, DPhil, professor of evidence-based medicine and director of the Center for Evidence-Based Medicine, Nuffield Dept of Primary Care Health Sciences, University of Oxford, United Kingdom, who was not involved in the study, told Medscape Medical News that the Dobson data indicate worryingly high rates of treatment-related "injury and poisoning" (risk ratio, 3.37; 95% CI, 1.08 - 10.47), even after dose adjustment required in the elderly with poor renal clearance, and little benefit in that group.

"The results inform us that there is no benefit of using oseltamivir in the elderly, given there was no symptom-relieving effect in this age group (over 65 years)," Dr Heneghan said. He noted that the Dobson article confirms there is no evidence that oseltamivir reduces pneumonia.

"The use of lower respiratory tract complications requiring antibiotics is not a clinically relevant outcome. Much of the reported effect on this outcome is driven by bronchitis, a condition for which antibiotics are not indicated, and acute bronchitis is often an indicator of respiratory syncytial virus, not influenza. We know from the results of a Cochrane systematic review that there is limited evidence to support the use of antibiotics in acute bronchitis."

Cautious Conclusions Applauded

Dr Dunn said, "I was impressed that Dobson et al provided a careful explanation of the [ITT] analysis and the difference between evidence of efficacy vs evidence of effectiveness in a clinical setting. The conclusion statements also make note of the importance of treatment strategies that take into account the balance of benefits and harms in the context of a clinical setting. These careful and considered conclusions are a departure from some of the concluding statements I have seen in previous reviews of the evidence."

Dr Monto added, "We know that oseltamivir works best when given early. Therefore, it is inappropriate, especially in those who are at high risk of developing complications, to wait for an absolute diagnosis. In this, we are gratified by our finding of the relatively low frequency of side effects produced by the drug. In these recommendations, we agree totally with that of [Centers for Disease Control and Prevention]."

This study was funded by the MUGAS Foundation through an unrestricted grant from Roche Pharmaceuticals. Dr Monto reported receiving fees from Biocryst and Roche outside of the submitted work. Dr Whitley reported receiving fees as a board member of Gilead Sciences (which holds the Tamiflu patent) and funding for travel from Roche to attend an Influenza Resistance Committee meeting. Dobson's salary was paid in part by a grant from MUGAS to the London School of Hygiene & Tropical Medicine for work on this project. Dr Cowling has received research funding from MedImmune and Sanofi Pasteur and consults for Crucell. Dr Jefferson has acted 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. Dr Jefferson has acted as consultant for Roche, GlaxoSmithKline, and Sanofi-Synthelabo, and in 2014 was retained as a scientific adviser to a legal team acting on the drug oseltamivir. The other authors and commentators have disclosed no relevant financial relationships.

Lancet. Published online January 29, 2015. Article abstract, Comment extract

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