BOSTON, Massachusetts—The Vioxx (rofecoxib) debacle was just the tip of the iceberg, and there will likely be other such disasters in the future because of fatal flaws in the way new drugs are tested and marketed, said Donald W. Light, PhD, MS, a professor of comparative health policy at the University of Medicine and Dentistry of New Jersey in Newark. He presented at the annual meeting of the American Sociological Association in Boston.¹

"Drug disasters are literally built into the current system of drug testing and approvals in the United States," he said. Moreover, "recent changes in the system have only increased the proportion of new drugs with serious risks."

Vioxx approval: the back story

Vioxx manufacturer Merck & Co, Inc voluntarily withdrew Vioxx from the market on September 30, 2004, after the Adenomatous Polyp Prevention on Vioxx (APPROVe) study was halted due to evidence for an increased risk in heart attack and stroke among patients taking the drug for ≥18 months. What followed were intense scrutiny and FDA hearings regarding the safety/risk profile of the remaining coxibs as well as traditional NSAIDs. This resulted in the addition of sweeping black box warnings on selective and nonselective cyclooxygenase inhibitors and the withdrawal of Bextra (valdecoxib).

According to a 1999 report for the Institute of Medicine, adverse drug reactions are the fourth leading cause of death in the United States and that >2 million serious reactions occur every year.

Problems inherent in FDA’s drug approval system

The existing testing system evaluates the effectiveness of new drugs based on their effects compared with placebos instead of using current approved drugs as benchmarks of efficacy. Systematic reviews indicate that one in seven new drugs is superior to existing drugs, but two in every seven result in side effects serious enough for action by the FDA, including black box warnings, adverse reaction warnings, or even withdrawal of the drug.

Based on such a system, new drugs are twice as likely to harm patients as to provide them with benefits superior to existing drugs. Moreover, pharmaceutical companies frequently design their trails to minimize evidence of toxic side effects by sampling from a healthier population atypical of patients who will actually take the drug. The trials are run long enough to pick up main effects, but not to detect some long-term side effects. Approvals are based on these data, so drugs with harmful effects sometimes get through.

"Based on our current system, the designation of 'safe and effective' on today's new drugs could be replaced with, 'apparently safe based on incomplete information, and more effective than a placebo,'" Dr. Light said.

He cites serious underfunding of the FDA, resulting in a dependency on the pharmaceutical industry to pay its staff. In return for drug company’s funding, the industry expects faster reviews, which can potentially fail to identify serious long-term side effects.

"Speed-up reviews for safety have more than tripled the number of 'black box warnings' of side effects or withdrawals after drugs are on the market. Despite recent reforms to strengthen the FDA's role in protecting the public from harmful drugs, the harm-benefit ratio is worsening due to these reviews and relaxed rules that allow companies to promote drugs for unapproved uses."

Congress, Wall Street both cause many FDA problems

Lee Simon, MD, of Harvard Medical School in Boston and a former FDA division director agreed that flaws in the current system will pave the way toward more Vioxx-like situations. “The best ways for companies to get drugs approved is to study niche populations and then do more studies postapproval,” he explained. “What is studied is not what is treated and that has been inherent to the system forever.”

It’s not the FDA’s fault, Dr. Simon stressed. “Congress has legislative authority?not the FDA, [so] it is what Congress wants.”

When asked by MSKreport.com if the situation will get worse before it gets better, Dr. Simon responded “How much worse can it get?”

Another culprit is Wall Street. “The drug approval process has more to do with driving up stock prices than getting patients better. Nobody is yelling except professors, and Congress and Wall Street are pretty powerful. Nobody is speaking for patients.”

Reference

1. Light DW. Science safety and the legacy of the Vioxx disaster today. Presented at: American Sociological Association; August 1-4, 2008; Boston, Mass.