Jill Wechsler

The last few months of 2004 were marked by crises likely to affect pharmaceutical and biotech manufacturing for years to come. Safety data indicated that antidepressants may cause problems for young patients that warrant black box warnings, new labeling, and special packaging. Merck pulled its blockbuster COX-2 inhibitor Vioxx off the market because studies showed increased risk of cardiac events from long-term use of the drug. To cap it off, British regulators shut down Chiron's Liverpool vaccine plant due to product contamination, creating a serious shortage of flu vaccine in the US.

Members of Congress pointed fingers at lax FDA oversight, accusing the agency of trying to squelch staff warnings of these safety issues and ignoring signs of trouble at Chiron. Federal investigators sought evidence of unethical manufacturer behavior, as government officials and industry leaders weighed a range of messages emerging from these events:

• The nation's adverse event reporting and post-marketing surveillance systems are limited and slow to identify looming safety problems.
• Sponsors may need to provide much more safety data to bring to market treatments that patients may use for years.
• The US vaccine supply system is antiquated, unreliable, and in need of a major overhaul to prevent shortages and inequitable access.
• Perhaps regulators and policy makers should rethink efforts over the past decade to accelerate the drug approval process and streamline research requirements.

CHIRON CRISIS For some time now, the US health care system has been plagued by shortages of many vaccines for children and unpredictable supplies of influenza vaccines. Observers describe the nation's vaccine supply system as "very fragile" and "unreliable" — characteristics that have escalated with the departure of Wyeth Pharmaceuticals and other companies from flu vaccine production. Recent shortages prompted CDC to ramp up orders for this year, particularly to meet growing demand generated by the government's own flu vaccine campaign.

FDA officials rushed to England to see if there was some way to salvage any of the vaccine. Team Biologics investigators had inspected the Liverpool plant in June 2003 and found a number of manufacturing problems that appeared correctable. At that time, there was no evidence of contamination in finished doses, and Chiron said it would fix specific quality control shortcomings. But the plant had a history of manufacturing problems and had changed hands several times in the last five years. Chiron bought the facility from PowderJect Pharmaceuticals in July 2003 and spent $75 million to upgrade the facility — which may have been pouring money down a sinkhole.

In August 2004, Chiron acknowledged contamination problems with some vaccine lots but assured FDA that it was an isolated situation, easily remedied. In fact, just a few days before the shut-down, Chiron CEO Howard Pien told a Senate committee that it had addressed its contamination issues and would deliver flu vaccine as promised. FDA officials were waiting for a Chiron report when Britain's Medicines and Healthcare Products Regulatory Agency closed the plant for three months because it determined that Chiron could not ensure product quality.

RISKY BUSINESS The Chiron catastrophe spurred public interest in usually arcane production issues such as sterile vial filling and cell-based production. While US public health officials scrambled to find alternative supplies and encouraged prudent use of available doses, the situation spotlighted serious problems with the vaccine supply system. Health officials and policy makers wanted to know why FDA did not address Chiron's problems earlier. They examined why Adventis Pasteur and MedImmune are the only other licensed flu vaccine producers for the huge US market, a situation that limits possibilities for dealing with emergencies.