January 20, 2012 — An international team of medical experts is calling into question the safety and efficacy of the anti-influenza drug oseltamivir (Tamiflu), saying that a review of unpublished data shows inconsistencies and that the drug's maker, Roche, has failed to provide access to a substantial amount of data on the drug. The review was published online January 18 in the Cochrane Library.
Governments around the world have spent billions of dollars stockpiling oseltamivir and zanamivir (Relenza, GlaxoSmithKline) — neuraminidase inhibitor drugs that were recommended by the World Health Organization in 2002 as treatment in the event of an influenza pandemic.
The integrity of the data on this class of drugs has continued to be a subject of debate, however. In a previous Cochrane review published in 2008, researchers documented significant concerns about publication bias in trials for the drugs. Importantly, they reported that as much as 60% of patient data from phase 3 treatment trials for oseltamivir had never been published.
The unpublished data included a study involving 1400 people of all ages, representing the largest treatment trial ever conducted on oseltamivir.
"We are concerned that these data remain unavailable for scrutiny by the scientific community," said Tom Jefferson, MD, a Cochrane review author of both the previous analysis and the new analysis, and an independent epidemiologist based in Rome, Italy, in a press statement.
In this week's update of the previous review, Dr. Jefferson and researchers in the United States, Great Britain, Japan, and Australia analyzed previously unpublished data from 25 studies, including 15 on oseltamivir and 10 on zanamivir. Data from an additional 42 studies could not be reviewed because of insufficient information or unresolved discrepancies in the data, the authors note.
The data included clinical study reports and regulatory documents that were available either through available sources or Freedom of Information requests. The studies mainly involved adults during influenza seasons in both hemispheres. All of the studies that were reviewed were sponsored by the drugs' makers.
"We reasoned that regulatory data could help contextualise trial data, providing deeper insight than clinical study reports alone," the authors write.
Symptoms Reduced, but Hospitalizations Unchanged
The research on oseltamivir showed that the drug did reduce the amount of time to alleviation of symptoms by an average of 21 hours (95% confidence interval, −29.5 to −12.9 hours; P < .001). However, it failed to reduce the number of people requiring hospital treatment (odds ratio, 0.95; 95% confidence interval, 0.57 - 1.61; P = .86).
In a postprotocol analysis of 8 studies, the authors found that participants randomly assigned to receive oseltamivir in treatment trials had a reduced odds of being diagnosed with influenza (odds ratio, 0.83; 95% confidence interval, 0.73 - 0.94; P = .003), which they say was likely the result of an altered antibody response. The zanamivir trials did not show the same trend.
Biased Reporting of Adverse Events
Important inconsistencies in the evidence of neuraminidase inhibitor adverse events were meanwhile observed between the unpublished and previously published studies. For instance, Japanese regulatory documents have shown higher nervous-system-related and psychiatric adverse events among patients receiving oseltamivir compared with placebo groups, yet there is no mention of those data in published reports.
In the 2 most cited published reports of serious adverse events, one has no mention of the adverse events, and the other "stated that '...there were no drug-related serious adverse events,' " the authors note.
"[W]e found no published paper of an oseltamivir trial which reported nervous or psychiatric adverse events, except headache," they write.
Adding further speculation to the published oseltamivir research is the fact that Roche, when pressed by the British Medical Journal after the earlier report, admitted that some published papers on its drug were ghost written.
In a statement to Medscape Medical News, Roche said it provided the Cochrane group with access to 3200 pages of "very detailed information, enabling their questions to be answered."
"Roche has made full clinical study data available to health authorities around the world for their review as part of the licensing process. It is the role of global health authorities to review detailed information on medicines when assessing benefit/risk," the company stated.
"All completed Roche sponsored clinical studies on the safety and efficacy of Tamiflu are available as peer-reviewed publications or in summary form on www.roche-trials.com. More detailed clinical trial reports are available for use by investigators on a password-protected site, enabling researchers to verify the findings of these studies and publications relating to them."
Although the Cochrane authors may dispute whether the information provided to them answered their questions, they are clearly in agreement on the role of global health authorities, and suggest that this is where the ball is being dropped.
CDC Still Endorses Oseltamivir
Despite the ghost-written papers and adverse event reporting inconsistencies, top governmental agencies, including the US Centers for Disease Control and Prevention (CDC), continue to endorse oseltamivir, Dr. Jefferson told Medscape Medical News.
"The US CDC and the European CDC continue to quote trials of Tamiflu which we now know were ghost written," Dr. Jefferson said.
"They keep citing the evidence regarding adverse events, although they are aware of our misgivings and the fact that 60% of the evidence in treatment trials is unavailable and never been seen outside of Roche and perhaps 1 or 2 regulators."
Journal Reports "Absurdity" of the Discrepancies
A separate investigation published online January 17 by the British Medical Journal to coincide with the Cochrane review indicates that oseltamivir data were subjected to different standards from different regulatory agencies around the world, resulting in further conflicting impressions of the drug's efficacy.
The European Medicines Agency (EMA), for instance, provided only a portion of clinical study reports on oseltamivir drug trials to Cochrane, despite the fact that the agency was legally permitted to request the full reports from the manufacturer.
The EMA has since informed the British Medical Journal of its intentions to publish reports for all drugs submitted for approval in upcoming years.
In a press statement, Fiona Godlee, MD, editor-in-chief of the British Medical Journal, said the findings underscore the need for a more consistent approach to drug regulation when the global community is concerned.
"The discrepancies between the conclusions reached by different regulators around the world highlights the absurd situation we find ourselves in," she said.
"In a globalised world, regulators should cooperate and pool their limited resources. Otherwise we will continue to waste money and risk people's health on drugs that don't work."
Impending Influenza Epidemic Sped Up Drug Approval Process
Dr. Jefferson noted that the threat of a global pandemic and pressing need for a newer drug treatment likely played a big role in putting the review of neuraminidase inhibitors in the fast lane.
"In the documents we reviewed, the clear reason why the first drug of the neuraminidase inhibitor family, Relenza, was approved was they hadn't registered a new anti-influenza drug since 1988," Dr. Jefferson said. "It was now 1999, there was an impending threat of an influenza pandemic, and they thought they needed to move the field along and register this new drug."
The urgency should not justify the continued support of a drug when important questions are raised, however, suggested Peter Doshi, PhD, from Johns Hopkins University, Baltimore, Maryland, who is a coauthor of the review.
"For governments to support a manufacturer's claim without their own independent verification is dangerous," said Dr. Doshi.
"In an emergency, of course standards of evidence can change, but the clinical trials on Tamiflu were conducted over a decade ago, yet there is no indication that CDC and the Department of Health and Human Services, which support many of the manufacturer's claims, have done their own independent verification of the complete trial evidence."
Tim Uyeki, MD, a medical officer and epidemiologist from the CDC's Influenza Division, told Medscape Medical News that the agency cannot comment on unpublished data; however, he explained that the CDC's recommendations, based on guidance from the Advisory Committee on Immunization Practices, carefully consider the risks and benefits of a drug in the context of its public health need.
"The guidance for use of antivirals for influenza treatment in the US is based on a review of published data, including results of randomized controlled trials, observational studies, and consideration of groups at higher risk for influenza complications. There are some inherent limitations of observational studies, given that they are not controlled; however, they can be very informative," he said.
"There are abundant observational studies for hospitalized patients with seasonal influenza and from the 2009 H1N1 pandemic, and all of these suggest clinical benefit of antiviral treatment, particularly if the drugs are initiated early."
Dr. Uyeki added that the current lack of other treatments for influenza is indeed an important issue.
"One has to look at the evidence for benefits and what are available options," he said. "We don't have many other options right now for the treatment of influenza. We certainly need more antiviral drugs — drugs that work in different mechanisms of action — and other therapeutic approaches, such as combination antiviral therapy."
"Vaccination is the best way to prevent influenza, but it won't prevent all illness from influenza."
Seasonal influenza epidemics are associated with an estimated average of more than 200,000 hospitalizations per year in the United States, and a range of from about 3400 to 49,000 influenza-associated deaths per year, Dr. Uyeki said.
All Research Should Be Accessible, Regardless of Commercial Interests
The Cochrane report researchers said they supported the use of the drugs in serious or compassionate cases, but they called on regulators around the world to be more consistent in their approach to the accessibility of research results.
"The mechanism of action of oseltamivir should be independently researched, with special regard to any direct central action of the drug Tamiflu, until a clear picture of its effects on influenza complications, transmission and action on antibodies can be clarified," they write.
"We all, as taxpayers, have a stake in this drug," Dr. Jefferson said to Medscape Medical News. "No other drug that I can think of is being stockpiled in the US."
"We cannot tolerate a situation where unnamed people make decisions on drugs that effect all of us."
The study received funding from the National Institute for Health Research Health Technology Assessment Program in the United Kingdom. Dr. Jefferson was an ad hoc consultant for F. Hoffman-La Roche Ltd from 1998 to 1999. He receives royalties from his books published by Blackwell and Il Pensiero Scientifico Editore, none of which are on neuraminidase inhibitors. He is occasionally interviewed by market research companies for anonymous interviews about phase 1 or 2 products unrelated to neuraminidase inhibitors. Dr. Doshi has disclosed no relevant financial relationships.
Cochrane Library. Published online January 18, 2012. Abstract
BMJ. Published online January 17, 2012. Abstract
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