

Is someone to blame in flu vaccine debacle? By Julie Appleby and Julie Schmit, USA TODAY As flu season neared in late September, the drugmaker at the center of the vaccine shortage radiated confidence. Doses of flu vaccine at a Chicago pharmacy. By Tim Boyle, Getty Images Only four weeks earlier, Chiron had surprised public health authorities and its investors when it disclosed tests that showed about 4 million doses of its Fluvirin vaccine were contaminated. But Chiron said that the rest of the production at its Liverpool, England, factory was fine, and it expected further tests to confirm that. The company quietly resumed shipping its flu vaccine to U.S. distributors and publicly maintained that it would be able to supply half of the USA's flu vaccine. When it started shipments in September, Chiron expected the Food and Drug Administration would agree. Much was riding on Chiron being right. The world's No. 2 flu vaccine maker had boosted production about 30% for the year. Public health officials had their sights set on providing a record 100 million vaccine doses this winter and Chiron, along with Aventis Pasteur, were the only flu-shot suppliers. And the company's distributors were eager to get the vaccine so they could fill orders from doctors' offices, hospitals and clinics nationwide in time for peak vaccination season, October and November. All those expectations were dashed on Oct. 4, when British regulators suspended Chiron's license to make Fluvirin over concerns about its manufacturing practices at the Liverpool plant. On Oct. 15, FDA officials backed the British, declaring all of Chiron's Fluvirin unusable because they couldn't guarantee its safety. Now, both Chiron and the FDA's oversight are under scrutiny as Congress, the Justice Department and the Securities and Exchange Commission investigate what led up to the nation's biggest flu vaccine shortage — and who, if anyone, is to blame. Congressional investigators have summoned the key players to Washington for hearings on Wednesday and Thursday. (Related story: Sick days dwindle, disappear for many) That the vaccine did not get to consumers is testament to a safety process that worked, say some industry consultants and regulators. (Related: Timeline of Chiron events) But the Chiron case raises questions about whether consumers came close to getting vaccine that two nations' regulators now say cannot be considered safe. Chiron said in July that the FDA had approved its first shipment of 1 million doses to distributors. Release to customers awaited only Chiron's completion of final quality-control testing and delivery of results to the FDA. "I would not be surprised if the FDA takes a serious look at its oversight procedures for vaccine manufacture overseas," says Ron Davis, a preventive medicine physician who sits on the American Medical Association's board of trustees. Today, Chiron's distributors say they're storing more than 6.5 million doses of Fluvirin under quarantine in their warehouses, rather than the 1 million that has been widely reported. The FDA last week sent hundreds of pages of documents to Congress, which have not been made public. Chiron and the FDA declined to provide interviews for this story. Questions likely to be raised by congressional investigators include: •Why didn't FDA inspectors travel to Britain immediately after Chiron reported its problem in late August? The FDA previously inspected the Liverpool plant's manufacturing practices in June 2003, just before Chiron bought it, and raised concerns then. In 1999, the agency also warned a previous owner about quality-control problems at the plant. After Chiron disclosed its contamination problem on Aug. 26, the company said it would delay releasing any Fluvirin until it had completed more tests. FDA officials have said the contamination was caused by a bacteria called serratia marcescens, which can be deadly to people with compromised immune systems. The FDA decided to have weekly teleconference calls to monitor Chiron's progress and await the company's final report. Coincidentally, FDA inspectors were at the plant for another matter when Chiron announced the contamination. They "looked at the records, made some suggestions," said acting FDA Commissioner Lester Crawford in a mid-October press conference. Then they left. When asked at that press conference whether the FDA inspectors should have stayed around longer, Crawford said no. "We followed standard procedures, and this is the way we've always done it, and it has worked very well in the past," he said. "It was our expectation, based on our communication with Chiron, that the problem would be cleared up," Crawford said. Some now say the FDA trusted Chiron too much. "The FDA should have been on the ground" the day after the contamination was announced, says David Webster of the Webster Consulting Group, a consultant to the pharmaceutical industry. "It's cause for concern ... that the FDA was relying strictly on the company ... instead of independently verifying compliance." •Is the FDA too reliant on vaccine makers to test vaccine and report problems? Manufacturers do most vaccine testing because it would be impractical for the FDA to test every batch of every vaccine made. The companies conduct tests for potency and sterility, among other things, and share the results with the FDA. Vaccine makers and regulators test samples of batches, rather than each individual dose. It is impossible to test each dose because individual vials would have to be opened, making all of the vaccine unsterile. A vaccine maker cannot release vaccine without the FDA's approval, which largely rests on the agency's review of the manufacturer's records. The FDA says it does not usually test the final vials of vaccine, but does perform some tests when the product is in bulk form. Government authorities say the contamination of Chiron's vaccine appeared to occur during the vial-filling stage, one of the trickiest parts of the process because containers have to be open to receive vaccine. Even after the British suspended Chiron's license, the company maintained that the contamination was confined to the 4 million doses announced in August. FDA defends actions The FDA's Crawford has described his agency's oversight of vaccine production as "fail-safe." "We would have found the problem," he said at a press conference about the Chiron case last month. Some critics of the drug industry are not so sure. "It seems pretty clear that the FDA was not going to pull the plug," says professor Alan Sager of Boston University's School of Public Health. "But we will never know." Until the British acted, the FDA had not scheduled a visit to the plant. The FDA says Chiron's final report, which it received the same day it learned of the British action, raised red flags. Only after that did the FDA send inspectors to the plant. That inspection led the FDA to declare that it "found significant deficiencies in quality control and concerns regarding the test results." The agency said it could not "adequately assure the sterility" of the vaccine. That was a sharp change from the optimism that had surrounded Chiron's efforts through September. On Sept. 28, Chiron CEO Howard Pien told a U.S. Senate committee that the company still expected to provide the U.S. market in early October with 46 million to 48 million doses of Fluvirin. On the same day, British regulators were at the Liverpool plant doing the inspection that would make that impossible. In late September, Chiron resumed shipping to at least two U.S. distributors, FFF Enterprises, and its biggest, Henry Schein. Neither distributor received shipments in August, they say. The distributors had signed agreements with Chiron not to release the vaccine until Chiron gave them final approval. When Chiron resumed shipping, "We thought everything was all right," says Luke Noll, marketing manager of FFF Enterprises. After its July press release disclosing shipment of its first 1 million Fluvirin doses, Chiron never again publicly announced how many doses were in the USA. But five of seven Chiron distributors tell USA TODAY they are storing 6.5 million doses in the USA. In response to an inquiry from the newspaper, Chiron said there are more than 6 million in the country but would not be more precise. The quarantined doses are expected to be destroyed. The documents that the FDA has given Congress may explain how vaccine became contaminated at the Chiron plant. "It could have been as simple as a leak in the ceiling that no one noticed, although I don't think it was that simple," says Larry Pilot, who was the FDA's associate director for compliance when he left the agency in 1979. He is now an attorney with McKenna Long & Aldridge, whose clients include drugmakers. It may have been that Chiron failed to document every step of the manufacturing and testing process. If Chiron cannot prove it followed all quality-control procedures, the FDA and British authorities cannot guarantee the vaccine is safe — even if samples of batches show no contamination. During manufacturing, workers must write down exactly what is done, often at the time it is done, not hours or days later. Failure to document that specifications were followed, down to whether workers washed their hands often enough, could be enough for drugmakers or regulators to reject a batch of vaccine. "The FDA is the world leader at regulating drugs," says Robert Belshe, director of the Center for Vaccine Development at Saint Louis University in St. Louis. Based on what regulators have said publicly, "Chiron should have had better quality control," says Alex Kanarek, a Canadian consultant who specializes in regulatory compliance and is the former head of vaccine manufacture for Aventis in Canada. "The vaccine is not available because regulatory authorities are not convinced that the conditions under which the vaccine was made and tested guarantee a safe product." Still, as details of the flu vaccine problem emerge, regulators are likely to come under as much scrutiny as the company, Pilot says. "Was the FDA derelict in some way? Or, if there was a problem that could have been identified earlier, whose responsibility was it? Does it reflect an inadequacy in the law?" he asks. All of those questions need to be answered, Pilot says, so that "in the future, it doesn't happen again."