Safety problems roil pharma and FDA; blockbuster drugs turns out to be risky business, while contamination problems shut down flu vaccine production.

The past few months have been marked by crises likely to affect pharmaceutical manufacturing for years to come. First, experts decided that safety data does indicate that antidepressants may cause serious problems for young patients and warrant black box warnings, new labeling, and special packaging. Then, industry stalwart Merck had to pull "Vioxx" off the market when studies showed increased cardiac events related to long-term use of the drug. To cap it off, British regulators shut down Chiron's Liverpool vaccine plant, creating a serious shortage of flu vaccine in the United States.

Members of the US Congress pointed fingers at lax Food and Drug Administration oversight, accusing agency officials of trying to squelch staff warnings of these safety issues and ignoring signs of trouble at Chiron. 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;

* policies offering incentives for manufacturers to conduct pediatric studies may encourage sloppy research;

* the US vaccine supply system is antiquated and unreliable and needs a major overhaul to prevent shortages and inequitable access;

* regulators and policy makers should consider rethinking efforts during the past decade to accelerate the drug approval process and streamline research requirements.

Warnings for children

The debate about antidepressants has been escalating all year, capped by charges that FDA and manufacturers allegedly hid troubling adverse event data on the use of selective serotonin reuptake inhibitors (SSRIs) by children. The issue grabbed public attention in June when New York attorney general Eliot Spitzer challenged GlaxoSmithKline for concealing pediatric safety and efficacy data about "Paxil" (paroxetine). The Senate Finance Committee already was investigating FDA oversight of drug safety and shifted its focus to whether FDA improperly withheld information about SSRI adverse events. The House Energy and Commerce Committee grilled manufacturers and FDA officials on this issue at two hearings in September. A joint meeting of FDAs Psychopharmacologic Drugs and Pediatric Advisory Committees weighed all the evidence and recommended that antidepressants carry a black box warning about the increased possibility of suicidal behavior in young patients.

In October, FDA carried out the panel's recommendations by requiring that some 32 antidepressants on the market add black box warnings; revise the warnings and precautions sections of labeling; and provide Patient Medication Guides to patients through unit-of-use packaging. These policies will prompt major changes in labeling and packaging operations for manufacturers and may lead some firms to discontinue production of some older products. Immediate fallout appeared as physicians curbed SSRI prescribing for young patients. While that change may be appropriate in some cases, it also raised concerns that denying access by very ill children to these therapies could be more harmful than prescribing these medications too broadly.

Beyond all the charges and denials about inadequate disclosure and cover-ups, the debate about whether SSRIs cause suicidality has raised genuine concerns about the conduct of clinical research and FDA oversight of the process. Robert Temple, director of FDAs Office of Medical Policy, explained to the House panel how difficult it is for clinical trials of antidepressants to show efficacy, noting that FDA approved only Eli Lilly's "Prozac" (fluoxetine) for pediatric use out of seven products studied.

A related issue is whether FDA's pediatric exclusivity program allows pharma companies to conduct inadequate trials in the rush to meet patent deadlines. While Temple acknowledged in his testimony that sponsors generally design these studies "with good intent and according to high standards," he noted that the failure of a supplemental pediatric study to show efficacy is not nearly as devastating as failure in a preapproval efficacy trial. Marketers thus may sponsor too few pediatric studies to obtain clear results or recruit too few patients who fully meet enrollment criteria. FDA says it will require future pediatric studies of antidepressants to have three arms that compare the test drug with both placebo and Prozac to show more clearly if poor results arise from an ineffective drug or a poorly designed study.

FDA and other regulatory authorities also are reviewing extensive adverse event databases to see whether the SSRIs' effects on children show up in adults. Until now, researchers in the United States and the United Kingdom have not found data indicating increased risk of suicidality in mature patients, but they don't really know why there's such a big age-based difference. They want to see if various study designs can clarify these issues.

Chronic concerns

Congressional analysts expect to use their experience probing antidepressant safety in further investigating Merck's decision to halt production of its blockbuster COX-2 inhibitor Vioxx (rofecoxib). Legislators pounced on FDA for "silencing" an agency staffer who had expressed concerns about cardiovascular side effects, while federal investigators probed whether Merck withheld information from investors.

Ironically, the COX-2s took over the pain relief market during the past five years because these newer products don't cause the ulcers and gastrointestinal bleeding found in aspirin and ibuprofen. However, FDA approved COX-2 inhibitors on the basis of clinical trials that ran 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 withdrawal may be extensive. Analysts estimate that approximately 20 million US patients have used Vioxx since its approval in 1999, and almost 100,000 individuals took the drug for more than 18 months, resulting in some cardiovascular event. Liability claims could run more than $10 billion.

Industry critics are pointing to Merck's aggressive DTC advertising campaign 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 safety data for the whole class. House and Senate committees plan hearings next year on FDA oversight of drug safety issues, which are likely to revive proposals to establish a separate agency to oversee post-marketing safety issues.

FDA is scheduling an advisory committee meeting to address the larger issue of how much long-term safety data is needed to feel confident about marketing a therapy likely to be used by patients for years.

While the Vioxx experience may spur calls for more safety data on new drugs in this class, proposals to increase the length of studies and number of patients tested always create a dilemma. Overly extensive data demands may block a new drug from market if test costs escalate substantially, but new drug approvals on the basis of limited data may subject the FDA and marketers to attack if safety problems emerge later.

More reliable vaccines

For some time now, the US healthcare system has been plagued by shortages of vaccines for children and during flu season. Observers describe the nation's vaccine supply system as "very fragile" and "unreliable," characteristics that have escalated with the departure of Wyeth Pharmaceutical and other companies from flu vaccine production. Recent shortages prompted the Centers for Disease Control and Prevention (CDC) to ramp up flu vaccine supplies 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 involved signing up San Francisco-based Chiron to provide more than 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 license of the facility because of contamination problems with the entire production run. Although the United Kingdom stood to lose less than 20% of its annual flu vaccine supply, an amount that other manufacturers could fill, the shutdown was devastating to the United States, which had relied on Chiron for approximately hall of its 100 million dose order.