Тамифлю впаривается успешно

David H Newman, a physician researcher at the Icahn School of Medicine at Mount Sinai in New York City and editor in chief of TheNNT.com, a web publication for healthcare data reviews and summaries, has reviewed some of the numeric and interpretive differences between the Dobson analysis and a 2014 Cochrane review of neuraminidase inhibitors that did not find a benefit in terms of serious complications.3 He told The BMJ, “The CDC’s message sounds more emotional than scientific. We would love to have a treatment for influenza that works, but in reviews by independent groups—and the Dobson group does not appear to fit this description—the oseltamivir data consistently fail to demonstrate benefits.”

Newman said a recent independent meta-analysis of published and unpublished data regarding elderly people with comorbidities, by Mark Ebell and colleagues at the University of Georgia, was noteworthy.4 “These [patients] didn’t even derive a symptom benefit. No symptom reduction, no hospitalization reduction, no nothing. This is amazing, because it means that in the group who could most benefit, theoretically, they couldn’t even show that the one actual benefit of the drug was present.”

Tom Jefferson, a reviewer with the Cochrane group and a coauthor of the 2014 review,3 says that the Dobson meta-analysis fails on several fronts.5 In a blog posted on the website of Oxford University’s Centre for Evidence-Based Medicine, Jefferson (who has disclosed that in 2011-13 he acted as an expert witness in a litigation case related to oseltamivir) says that the Dobson paper was not preceded by a “written and publicly exposed” protocol that could be critiqued; nor did the authors provide an appraisal of the methodological quality of each study. He also criticizes the use of individual patient data “without reference to parent studies,” saying that in his Cochrane review of thousands of pages of clinical study reports he found that it was difficult to assess harms of treatment because “according to Roche you never know [whether] you are looking at toxicity of Tamiflu or at symptoms of influenza and the cards are mixed accordingly.” This led Jefferson and his colleagues to dub the problem of categorizing symptoms as “compliharms” in their Cochrane review. Other flaws he cited included lack of clear definitions of outcomes such as pneumonia, with a reliance on symptoms and antibiotic prescriptions, not chest x-ray pictures.

Newman says that the CDC’s promotion of oseltamivir to healthy people could actually increase harms and deaths. “The vast majority of flu deaths occur among people aged 75 and older,6 as well as individuals with serious underlying illnesses. By telling healthy people to get an antiviral within 48 hours, patients descend on emergency departments. During the 2009 summer swine flu outbreak, patients flooded ERs [emergency rooms] around the country. Most didn’t actually have the virus, and of those who did, most were not sick enough to need hospitalization.” Even so, says Newman, when patients with mild flu symptoms show up in the hospital, they vastly increase the spread of the virus simply because they inevitably sneeze and cough in rooms that are jammed with other people, some of whom are already immunocompromised.7 Death rates in emergency rooms, he said, increase when crowding occurs, as care of critically ill patients is compromised when doctors are spread thinly.8

John Ioannidis, professor of health research and policy and director of the Stanford Prevention Research Center at Stanford University School of Medicine, responded to claims that it was necessary to rely on observational data regarding mortality. He told The BMJ, “I don’t think [a randomized controlled trial] for hospitalized patients is unethical, and given the large burden of influenza it should be feasible to gather the numbers required if a committed effort is made, ideally from a federal agency sponsor.

“One strategy may be to perform a randomized trial on patients whose symptoms become severe after two days of their onset, the group where currently the observational meta-analysis shows no clear benefit . . . The trial would need careful monitoring with interim analyses in case it needs to be stopped early.”

Money: the CDC, the Dobson paper, and a PR firm

The CDC promotes the “Take 3” campaign to fight the flu. Step 3 of the campaign encourages people to “take flu antiviral drugs if your doctor prescribes them.”

The CDC Foundation, created by Congress to “connect CDC to the private sector to advance public health,” provides funding to the CDC. The foundation confirmed to The BMJ that the CDC received a directed donation from Roche via the foundation for the campaign, stating, “Roche provided a grant of $198 000 to CDC Foundation [which] has an administrative fee of 13.5%, so $174 800 was provided to [the CDC to] support qualitative research into influenza prevention and treatment messaging.”

This is not the only money the CDC takes from the industry. Unbeknownst to many, the CDC receives substantial industry funding through the CDC Foundation. A spokesperson said that over the past three years the foundation has received an average of around $6.3m from the industry a year, 21% of the foundation’s overall funding. Since 1995 the foundation has received funding from more than 150 corporate “partners,” including Gilead, which holds the patent on oseltamivir, as well as Genentech and Roche, the drug’s manufacturers.

Neither the CDC nor the foundation provided data on how much funding Roche, Gilead, and Genentech have donated to the CDC in addition to that for the Take 3 campaign.

A spokesperson for the foundation said, “Policies and procedures are in place to ensure CDC’s scientific independence. Projects . . . undergo a review and approval process . . . to ensure the project . . . has appropriate research methodologies, maintains CDC’s research independence, and does not present conflicts of interest.” Frieden added, “The CDC has a robust process of scientific review, including for ethical considerations regarding funding and [conflicts of interest].”

Marcia Angell, former editor in chief of the New England Journal of Medicine, told The BMJ that “the CDC has enormous credibility among physicians, in no small part because the agency is generally thought to be free of industry bias. Financial dealings with biopharmaceutical companies threaten that reputation.”

The Dobson study, cited by the CDC as support for its promotion of oseltamivir, was funded by the Multiparty Group for Advice on Science (MUGAS), which received an unrestricted grant from Roche for the study. A coauthor of the study, Arnold Monto, told The BMJ that the study was independent of both Roche and MUGAS, stating that neither they nor the study itself were influenced in any way by Roche and that neither MUGAS nor Roche saw the results of the study until they were released to the public.

However, three of the four coauthors of the Dobson meta-analysis have received speaker’s or consultancy fees, grants, or contracts from the manufacturers and patent holder of oseltamivir. Monto declared his funding from Roche. Richard Whitely declared his financial tie to Gilead, the patent holder. Stuart Pocock told The BMJ that he has received funding from several drug companies for cardiovascular research, including Gilead and Genentech, but that none of his funding was related to the study of antivirals for flu.

The protocol and other disclosures regarding the methods of the Dobson meta-analysis remain unpublished. Pocock declined a request from The BMJ for a copy of the study protocol, saying, “If you look across all meta-analyses published in medical journals you will find that the great majority do not publish a protocol. We conform to that standard practice. Our Lancet article Methods section defines the predefined variables we studied and the predefined methods of statistical analysis.”

Peter Doshi, a coauthor of the Cochrane review and an associate editor at The BMJ, said that it was true that meta-analyses in the absence of a systematic review often lack published protocols. However, he said that a protocol would seem to exist somewhere, because the methods presented in the publication were insufficient to explain the authors’ nuanced interpretation of their results. In particular, he asked how, without clinical study reports, the authors could have independently analyzed the definition of pneumonia in trials.

Additional conflicts are evident in a complex set of inter-related organizations that supported the Dobson study.9 Chris Vanlangendonck, managing director of Semiotics, a public relations firm based in Belgium, is listed as a co-founder of MUGAS, which received funding from Roche for the Dobson study.

MUGAS states that its goal is “review and statistical analysis of oseltamivir” and identifies the European Scientific Working Group on Influenza (ESWI) as the organizer of an invitation only meeting of MUGAS on 18 June 2013, reported by The BMJ,10 when oseltamivir data were reviewed. Monto is a board member of ESWI, which acknowledges on its website (www.eswi.org) that Roche also funded ESWI with an unrestricted grant. On its website MUGAS states: “Roche provided ESWI with an unrestricted grant. Neither MUGAS partners nor invitees received a fee or honorarium for their contribution and input. MUGAS builds on the shared concern to resolve scientific issues . . . and has no commercial objectives whatsoever.”

The contacts provided for both MUGAS and ESWI are at Semiotics, which lists among its staff a marketing specialist and an experienced ghost writer.

Semiotics told The BMJ by email, “Annual contributions from Roche equal 20% of the total annual company contributions or some 8% of ESWI’s total annual revenue, while Gilead contributed 2% to the budget of the latest ESWI Influenza Conference (Riga, September 2014).” The firm said that it cannot release information about the actual dollar expenditures.

Oseltamivir sales rose 54% in the final quarter of 2014, a news release by Roche said.11