intended to treat symptoms in patients suffering from the flu is essentially a waste of money, according to two new studies finding that the effectiveness of the antivirals is vastly overstated and the harms underplayed. The companies that make the drugs and the Centers for Disease Control and Prevention
are challenging those conclusions.
The studies stoke already heated concerns over the lack of accessibility to clinical trial information and loopholes in the drug approval processes in both the United States and Europe.
Fears of a flu pandemic in 2009 prompted government agencies around the globe to begin stockpiling Roche's Tamiflu (oseltamivir) and GlaxoSmithKline's Relenza (zanamivir), which the companies claim mitigate the symptoms and stop the spread of the flu virus in the body. The Cochrane Collaboration, which provides systematic reviews of research, started looking for data on the safety and effectiveness of the drugs. It took 4½ years, Cochrane officials said, to obtain the complete list of trials conducted on the drugs from the respective manufacturers.
Their reviews found no evidence to support that the drugs reduce pneumonia complications, led to fewer hospitalizations or could stop the spread of a pandemic. Moreover, some of the more worrisome side effects of Tamiflu—like the potential for psychiatric and renal problems and hypoglycemia—were understated.
The scientists analyzed data from 20 Tamiflu trials involving about 9,600 patients and 26 Relenza trials with about 16,600 patients. The results were published Thursday
in the journal BMJ.
Roche said the company fundamentally disagrees with the conclusions and that Cochrane only looked at 20 out of 77 of the trials available to them. “We do not consider the (Cochrane Acute Respiratory Infections) Group to be the final authority on the value of neuraminidase inhibitors,” Roche said in the statement, also pointing out that the U.S. Food and Drug Administration
, the CDC and the World Health Organization have all endorsed the medications.
The CDC says
that it continues to recommend the use of the neuraminidase-inhibitor antiviral drugs, and that the Cochrane review does not tell the whole story.
“It's only part of the evidence,” said Dr. Tim Uyeki, chief medical officer of the CDC's influenza division. The review bases its conclusions on outpatient data from healthy people with mild disease, which Uyeki says excludes observational data on hospitalized patients and those high-risk populations – like pregnant women, babies and people with chronic diseases - who have the most severe outcomes.
“We feel there is evidence that early treatment in hospitalized and high risk patients can be clinically beneficial in preventing severe outcomes,” he said. “The studies in the recent Cochrane review were statistically underpowered and not designed to assess that.”
However, Cochrane scientists and BMJ editors say the findings expose fundamental flaws in the systems and processes government agencies use to ensure the quality and safety of medications that are approved. The agencies, they argue, rely too heavily on the drug manufacturers, who have a vested interest in the results.
“The drugmakers have an irreducible conflict of interest when it comes to presenting the data from their studies,” said Dr. Fiona Godlee, BMJ editor-in-chief, during a news conference. “They are not incentivized to create a clear picture of the effectiveness and safety of their drugs at the moment.” The vast majority of trials are funded or conducted by industry or industry-paid experts, she said, and that leads to an overly optimistic view of the medications' benefits.
Others noted during the news conference that it is still routine—and entirely legal—for researchers to withhold the results of clinical trials, and that it's not uncommon to find methodological shortcomings in the design of the studies upon review. Gaining access to clinical trial data has historically been a complicated issue. Drug manufacturers have regarded the information as proprietary, making it challenging for outside groups to replicate the findings.
The push for transparency has been gaining traction, though, including several collaborative efforts in the past year. Relenza manufacturer GlaxoSmithKline started clinicalstudydatarequest.com
in 2013, and according to the company's website, Boehringer Ingelheim, Roche, Sanofi and ViiV Healthcare have committed to the data-sharing effort. The website alltrials.net
—launched last year in Europe by a group including BMJ, Cochrane the Dartmouth Institute for Health Policy & Clinical Practice—has requested that all past and present trials be registered and their results be reported. In January, Johnson & Johnson
entered an agreement to share clinical trial data through the Yale School of Medicine's Open Data Access Project, which will serve as an independent body to review requests from investigators and physicians seeking access.
Still, there is a long way to go, not only in gaining access to data on newer trials being conducted, but also on those from decades ago for drugs currently in use. Tamiflu came to market in 1999.
“This is a multisystem failure,” said Dr. Peter Doshi, assistant professor of pharmaceutical health services research at the University of Maryland and a part of the team reviewing the Cochrane research for publication in BMJ. It is assumed that both the CDC and FDA had access to the same 150,000-plus pages of data on Tamiflu and Relenza, he said during the news conference, but the federal agencies did not agree on the evidence supporting basic claims nor the potential risks of the drugs.
“When they are fundamentally at odds about the basic assumptions that have gone into billion-dollar stockpiling decisions, they need to reconcile those differences. That is completely unacceptable.”Follow Sabriya Rice on Twitter: @MHSRice