New Questions on Safety - Pharmaceutical Executive


New Questions on Safety
Vioxx, vaccines, and SSRIs: Today's bad news as tomorrow's agenda.

Pharmaceutical Executive

Ironically, COX-2s dominated the pain relief market in the last five years because they don't cause the ulcers and gastrointestinal bleeding that aspirin and ibuprofen sometimes do. But FDA approved COX-2 inhibitors based on clinical trials running less than a year, and the serious side effects, including elevated blood pressure, cardiovascular events, and liver toxicity, did not appear until months later.

The fallout from the Vioxx issue may be extensive. Industry critics point to Merck's aggressive DTC advertising for boosting Vioxx use despite safety concerns. Pfizer and other COX-2 marketers are trying to distance their products from Vioxx, but medical experts in the United States and Europe are calling for a thorough examination of the whole class. Congress plans hearings next year on drug safety issues; they are likely to revive proposals to establish a post-marketing safety agency separate from FDA's product approval process.

The larger question is how much long-term safety data is needed to confidently market a therapy that patients are likely to use for years. Merck obtained conclusive data on Vioxx's problems only after sponsoring a three-year post-approval study to test the product's efficacy in preventing recurrence of colorectal polyps. The company halted a trial of 2,600 patients after 18 months, when preliminary results revealed that 3.5 percent of patients taking Vioxx experienced thrombotic events, compared to 1.9 percent in the placebo arm.

Son of BioShield
Although the Vioxx experience may spur calls for more long-term safety data on new COX-2 drugs coming down the pipeline, proposals to increase the length of studies and number of patients tested always create a dilemma. Overly extensive data demands can block a new drug from the market if trial costs escalate too much, but new drug approvals based on limited data can subject FDA and marketers to criticism if safety problems later emerge.

More Reliable Vaccines For some time now, the US healthcare system has been plagued by shortages of vaccines during flu season. Observers describe the nation's vaccine supply system as "very fragile" and "unreliable," characteristics that have escalated with the departure of major pharma companies from the vaccine business. Flu vaccine shortages in 2000 and 2003 prompted the Centers for Disease Control and Prevention (CDC) to ramp up supplies for this year, particularly to meet growing demand generated by the government's own campaign encouraging more patients to get a shot.

A key element in CDC's efforts involved signing up San Francisco-based Chiron to provide 40 million or more doses of flu vaccine this fall from its newly acquired Liverpool plant. The plan fell apart when British regulatory authorities suspended the facility's license because of "issues with systems and processes" designed to ensure product quality. While Britain stood to lose less than 20 percent of its flu vaccine supply—an amount that other manufacturers could fill—the shutdown is devastating to the United States, which had relied on Chiron for about half of its order of 100 million doses.

FDA officials, caught by surprise, rushed to England to see if there was some way to salvage any vaccine. Agency investigators had inspected the Liverpool plant in June 2003 and found what they thought were correctable manufacturing problems. At that time, there was no evidence of contamination in finished vaccine, and Chiron said it would fix the quality-control shortcomings. But the British plant had a history of manufacturing problems, and although Chiron spent $75 million to upgrade the facility after buying it from PowderJect Pharmaceuticals in 2003, it may have been pouring money down a sinkhole.

In August, Chiron acknowledged contamination problems with actual vaccine lots, but it assured FDA that the situation was easily remedied. In fact, just days before the shutdown, CEO Howard Pien told a Senate committee that Chiron had addressed its contamination issues and would deliver vaccine as promised. Agency officials were awaiting a Chiron report when Britain's Medicines and Healthcare Products Regulatory Agency closed the plant for three months because inspectors felt Chiron couldn't ensure product quality.


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