Regulatory Beat: Vaccine Manufacturing and Safety in the Spotlight

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.

Jill Wechsler

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.

A key element in CDC's efforts to boost supply was enlisting San Francisco-based Chiron to provide over 40 million doses of flu vaccine this fall from its newly acquired Liverpool plant. The plan fell apart in October when British regulatory authorities suspended the facility's license due to contamination problems affecting the entire production run. While the Brits stood to lose less than 20% of their annual flu vaccine supply, an amount that other manufacturers could fill, the shutdown was devastating to the US, which was relying on Chiron for about one-half of its 100 million doses.

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.

Wyeth exited the field in 2002 after years of losses due to low demand and low prices. Flu vaccine has to be reformulated each year and cannot be stored for future use. In its last production season (2002-3), Wyeth threw away 7 million of 21 million doses. European and other markets are more attractive to vaccine makers because some governments agree to purchase a certain amount of vaccine each year to reduce manufacturers' risk, and companies face fewer lawsuits and liability concerns abroad. Congress recently added vaccines for influenza and hepatitis A to the Vaccine Industry Compensation Program, but more may be needed to boost US vaccine production (see "Building Biodefenses"). While the federal government still is not likely to take over vaccine distribution and production, as some industry critics propose, this latest incident could prompt federal agencies to play a more prominent role in the vaccine market and to examine other ways to spur production:

• Expand government guarantees for vaccine purchase to cover unused doses that manufacturers often have to discard every year.

• Provide grants and support for manufacturers adopting modern vaccine production techniques. NIH officials are offering up to $150 million in financial incentives to encourage pharma companies to develop modern flu vaccine production technologies, such as cell-based cultures and DNA engineering. Everyone agrees that it's vital to shift away from today's old-fashioned, egg-based systems, which are slow and difficult to change.

• Reform vaccine oversight and market. A report from the National Vaccine Advisory Committee, which appeared in October as the flu vaccine crisis was emerging, recommends dropping price caps on vaccines for children, improving vaccine coverage by payers and insurers, and seeking greater harmonization in US and foreign vaccine approval requirements to increase supplies in an emergency.

DRUG SAFETY

Meanwhile, Congress and federal agencies will be focusing more on drug safety and quality issues in coming months. FDA and other regulatory authorities are reviewing extensive adverse-event databases to see whether the adverse effects of antidepressants on children show up in adults. Until now, researchers in the US and the UK have not found evidence of increased risk of suicidality in mature patients, but they don't know why there's such a big age-based difference. They want to see if different study designs can clarify these issues.

FDA also is scheduling an advisory committee meeting to address the larger question of how much long-term safety data is needed for therapies likely to be used by patients for years. Merck obtained conclusive data on Vioxx's safety problems from a three-year, post-approval study for preventing the recurrence of colorectal polyps. While the Vioxx experience may spur calls for more safety data on emerging therapies in this class, proposals to increase the length of studies and number of patients tested always create a dilemma. Overly extensive test demands can block a new drug from market if costs escalate too much, but new drug approvals based on limited data can subject FDA and marketers to attack if safety problems later emerge.

Building Biodefenses

Although biotech and pharma companies have long sought stronger liability protection for vaccines and drugs, legislation has been stuck on Capitol Hill for years. Congress approved Project BioShield in July only after dropping key liability provisions. Now Senate Judiciary Committee chairman Orrin Hatch (R-Utah) and Sen. Joseph Lieberman (D-Conn) are hoping to gain approval of a BioShield II bill next year that would create more incentives for industry to develop vaccines and other counterterrorism treatments.

Without added legal safeguards, manufacturers are likely to remain fairly lukewarm to the BioShield program, leaving the field to small biotech firms. HHS recently awarded $232 million in contracts to companies developing new vaccines against smallpox, plague, and tularemia, but the recipients are fairly small, and two are outside the US. The Senate Judiciary and Health committees held a hearing on BioShield II this fall to build support for tax incentives, intellectual property protections, and liability shields to spur more counterterrorism product development. Some health experts also want to extend BioShield protections to companies that develop antibiotics and general vaccines to protect the nation against a flu pandemic or other health crisis.

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634. jwechsler@advanstar.com.