MELBOURNE, AUSTRALIA—A warning letter from the U.S. Food and Drug Administration (FDA) to Australian vaccine maker CSL Biotherapies has shaken confidence in the country's biotech superstar. The 15 June letter accuses CSL of failing to adequately investigate why its Fluvax influenza vaccine last year caused a sharply elevated rate of febrile convulsions in some children under the age of five. "There was no analysis of all critical parameters and critical processing steps to try to determine differences in the 2010 lots associated with Adverse Event reports compared to lots from previous seasons" the letter states. The letter gave CSL 15 days to respond to its concerns or risk losing its license to sell Fluvax in the United States, where it is marketed under the name Afluria.
"We are taking the warning letter very seriously," said Jeff Davies, executive vice president of CSL Biotherapies, in a prepared statement. "Our technical team is in the process of preparing more substantive detail about our corrective actions to meet the FDA's requirements."
CSL Biotherapies is one of Australia's top biotech performers, with 2010 revenue of $4.8 billion; worldwide sales of Fluvax were $130 million, including $56 million in the United States. Following adverse reactions to the flu vaccine reported in 2010, FDA sent inspectors in June to CSL's manufacturing plant in Melbourne. After a second visit last March, FDA issued its warning letter, which stated that CSL's Quality Control Unit had failed to "fulfill its responsibility to assure the identity, strength, quality, and purity of your monovalent influenza bulks and final drug products."
A recent study by Paul Armstrong at the Department of Health, Western Australia, and colleagues reported that the rate of febrile convulsions among young children was 3.3 per 1000 doses, 200 times that reported in a U.S. influenza vaccine safety study. The same study indicated that febrile convulsions were linked to CSL's vaccine but not to equivalent vaccines such as Influvac and Vaxigrip.
In the June issue of the journal Vaccine, Christopher Blyth at the University of Western Australia and colleagues found that Fluvax (but not other flu vaccines) triggered the release of high levels of cytokines in blood cells isolated from the children who had febrile seizures. Cytokines are natural molecules of the immune system that induce fever. Investigations by independent labs and CSL have failed to pinpoint why Fluvax appears to sharply raise cytokine levels.
According to FDA's letter, CSL's manufacturing methods hindered the ability to root out the cause of the adverse reactions. CSL prepares the vaccine by killing flu virus and splitting it. The degree of splitting could influence how the vaccine triggers an immune response, said one influenza vaccine expert who asked for anonymity. But FDA says the degree of splitting was not determined in different batches. "You failed to determine optimal splitting conditions for new virus strains before the strains are used in production," FDA said in its letter to CSL. FDA also claimed that the splitting agent used to fragment the virus, sodium taurodeoxycholate (TDOC), had failed a test to confirm the identity of the chemical. Another FDA criticism is that CSL failed to identify what FDA calls "dark particles" in some vials. Furthermore, FDA stated that CSL failed to adequately document its investigative procedures into why the vaccine caused adverse reactions.
A CSL spokesperson told ScienceInsider in an e-mail that investigations by the company and by Australia's drug regulator, the Therapeutic Goods Authority (TGA), so far have not identified any contaminant in the manufacturing process. Furthermore, they pointed out that although TDOC failed a first test, it passed a subsequent test for its identity. "We hope to be in a position to draw some conclusions [about the cause of the elevated rate of febrile convulsions] in the next few months and will be fully transparent about our findings," wrote the CSL spokesperson.
The concerns about Fluvax are causing angst in Australia's biomedical research community. "I've never been convinced by the cost-benefit equations for vaccinating healthy people or children against influenza, but one of the things I didn't think was that there was a problem with the manufacturing process," says Peter Collignon, director of Infectious Diseases at Australian National University Medical School in Canberra. He says that he's troubled by the fact that FDA, not TGA, first aired concerns about the vaccine. "This raises questions about the transparency of our own regulator," he says.
On 21 June, TGA revealed that it had sent letters since May 2010 to CSL after five audits flagged problems ranging from "inadequate investigations" to "poor management of corrective and preventative actions", and "inadequate" cleaning and testing regimes. Davies of CSL told the media that TGA was "fully aware" of the issues, but didn't feel it was appropriate to release correspondence with the regulatory agency.
FDA's warning letter raises the stakes. It "means they'll either get it right pretty quickly or they won't be making these vaccines anymore," says Collignon. "If you can't market in the U.S. because it's not safe enough, then it's not going to be very satisfactory for Australia either."