Reports probe Tamiflu benefits, call for clinical data transparency

Dec 9, 2009 (CIDRAP News) – In an update of a review on the role of neuraminidase inhibitors in seasonal flu prevention and treatment, the authors reversed a previous conclusion that oseltamivir (Tamiflu) prevents complications like pneumonia in healthy patients because they were unable to reconstruct the data in one of the key studies that found a benefit.

The review was published today in the British Medical Journal (BMJ), along with an investigation that the journal conducted with England's Channel 4 News on the authors' attempts to obtain the raw data from Roche, which supported the earlier studies and is the maker of Tamiflu.

The BMJ's investigative report and an accompanying editorial say difficulties the review authors had in verifying the data cloud government stockpiling policies and point to other problems with drug company transparency in the drug approval process and medical journal publishing practices. They also wrote that an earlier Cochrane Library review, published in 2006, should have been more rigorous.

Though today's BMJ articles focus on seasonal flu and healthy patients, they may have implications for pandemic flu, because Tamiflu is the drug of choice for managing H1N1 infections, especially in those with severe illness and those at high risk for complications.

Analysis includes 20 studies
The research team, which included experts from Australia and a doctoral student from the Massachusetts Institute of Technology, analyzed 20 published trials on neuraminidase inhibitor use in seasonal flu that focused on prevention, treatment, and adverse reactions. However, they dropped eight trials that were included in the 2006 review, because they were never published and the researchers weren't able to verify the results. According to the BMJ investigative report, Roche wouldn't send the authors the raw data without a signed confidentiality agreement.

They concluded that neuraminidase inhibitors have a modest effect against seasonal flu symptoms in healthy adults, but a scarcity of good data undermines the previous finding that Tamiflu is useful in preventing flu complications. The investigators wrote that independent randomized trials are needed to resolve uncertainties.

During negotiations with the authors over the raw data, Roche sent them a group of observational studies. An analysis of those studies in the same issue of BMJ found that oseltamivir may reduce the risk of pneumonia in healthy patients who have flu, but the benefit is small and side effects and safety should be considered. The authors of the analysis also said interpreting the observational studies was difficult, because some patients were included in more than one study.

In an editorial in the same issue of BMJ, the journal's editor-in-chief, Dr Fiona Godlee, and Mike Clarke, director of the Cochrane Centre in Oxford, England, wrote that Roche hasn't done anything wrong by current pharmaceutical standards, but they said the current system isn't working and "gives a false sense of security."

They wrote that drug company studies are often shrouded in secrecy and aren't always subject to full independent review. They call for more publicly funded trials and said governments should pass laws requiring access to raw data on licensed drugs.

Data access limited
Fred Hayden, MD, a virologist at the University of Virginia and coordinator of influenza activities at the Wellcome Trust, an independent medical research funding charity based in London, was the corresponding author of an analysis that included raw data from some of the Roche-supported studies that Australian researchers couldn't obtain from Roche. That report, published in a 2003 issue of Archives of Internal Medicine, has been widely use to support Tamiflu use for preventing flu-related pneumonia and hospitalizations. Hayden said that after several moves he was unable to track down the raw data and advised them to request it from Roche.

Hayden told CIDRAP News that the 2003 findings are still valid and that he supports the researchers' access to the primary data. Roche said in a response to BMJ that it would provide the raw data to researchers who have a legitimate need for it on a password-protected Web portal. "There's no question that this is the right thing to do," Hayden said.

The new BMJ review might send a confusing message to clinicians who are in the midst of treating pandemic H1N1 patients, Hayden said. He said the review focuses on uncomplicated seasonal influenza, and he cautioned physicians not to generalize too broadly from it in their management of pandemic H1N1 cases.

Studies on patients with H5N1 avian influenza infections from different countries have shown that early oseltamivir treatment can reduce mortality, and clinicians are seeing the same pattern for patients with pandemic H1N1 flu.

Hayden is part of a World Health Organization (WHO) panel of antiviral experts that met in June to update WHO guidance for pandemic H1N1 management. He said the group meets again in January to review the most recent data, and he doesn't think the BMJ review will have much of an impact on the discussions.

WHO evaluating reports
Charles Penn, PhD, a scientist with the WHO's global influenza program, told CIDRAP News that the WHO is still evaluating all of the BMJ reports to see how they might affect its antiviral guidelines. However, he said the review isn't based on any new evidence and that its conclusions contain findings about neuraminidase inhibitor use that are already well known, such as a modest benefit in otherwise healthy patients.

He pointed out that the pandemic H1N1 virus is affecting a different age range than seasonal flu, with a small number of very severe cases, including some involving viral pneumonitis. Researchers are building up a body of evidence from 6 months of clinicians' experience in managing pandemic H1N1 patients, and the data suggest oseltamivir is having an impact on severity and hospitalizations.

When queried about a response from the Centers for Disease Control and Prevention (CDC) to the BMJ review, CDC spokesman Tom Skinner referred CIDRAP News to a recent perspective article by Tim Uyeki, MD, MPH.

Uyeki, a medical epidemiologist in the CDC's Influenza Division, wrote in a Nov 18 article in the New England Journal of Medicine that evidence "supports the benefit of neuraminidase inhibitors (oseltamiviror zanamivir) in reducing complications, including deaths, among hospitalized patients with 2009 pandemic influenza A (H1N1)."

Uyeki cited three observational studies of oseltamivir in seasonal flu that showed reduced mortality in hospitalized patients.

"Taken together," Uyeki concluded, "although data are limited, findings of observational studies all point in the same direction, suggesting benefit of early neuraminidase inhibitor treatment for hospitalized influenza patients as well as for patients presenting >48 hours after illness onset."

Some conclusions already accepted
Vincent Racaniello, PhD, professor of microbiology at Columbia University and author of Virology Blog, told CIDRAP News that the BMJ studies are well done and the conclusions are valid, but he said scientists have known for a long time that neuraminidase inhibitors are marginally effective. "They were approved because there are no other antivirals available," he said. "In people with lab-confirmed influenza, they work about 70% of the time in reducing symptoms by a day. That's been known for years and these meta-analyses confirm that."

He said the new BMJ review's conclusion that there is no benefit from postexposure prophylaxis for influenza-like illness contradicts earlier studies, but he said some of the illnesses might not have been flu and may not have been affected by neuraminidase inhibitors. "That’s one reason why the authors of this study call for more trials," Racaniello said. The other reason they support more study is because they're not sure that the drugs don't prevent complications, he added.

The issue the BMJ articles raise about the release of clinical trial data is "terrific," Racaniello said. "This is immediately relevant because, for example, many people would like to see the results of H1N1 clinical trials before deciding to take the vaccine. They aren't widely available, yet the vaccine is in use," he added.

Racaniello predicted that the new review won't have much affect on policies regarding the use of neuraminidase inhibitors. The drugs help, even if experts aren't sure if they help with complicated influenza, he said. "The study emphasizes the fact that we don’t have very good drugs against influenza and we need to have more. Some are in development, but it's not enough."

Jefferson T, Jones M, Doshi P. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 2009 Dec 8;339 (Early online publication) [Full text]

Cohen D. Complications: tracking down the data on oseltamivir. BMJ 2009 Dec 8; web extra [Abstract]

Freemantle N, Calvert M. What can we learn from observational studies of oseltamivir to treat influenza in healthy adults? BMJ 2009 Dec 8;339 [Full text]

Godlee F, Clarke M. Why don't we have all the evidence on oseltamivir? BMJ 2009 Dec 8;339 (Editorial) [Full text]

See also:

Uyeki T. Antiviral treatment for patients hospitalized with 2009 influenza A (H1N1). N Engl J Med 2009 Nov 18 [Full text]

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