FDA faces challenge of dual responsibilities

Direct-to-consumer advertising was lucrative for Merck Pharmaceutical Co. To the sweet sound of The Rascals’ “It’s a Beautiful Morning,” we watched Dorothy Hamill skate pain free thanks to her Vioxx. The ads helped Merck rake in more than $2.5 billion a year from the drug.

On Sept. 30, 2004, Merck voluntarily withdrew the drug because of an excess risk of heart attack and stroke, which showed up in a study looking at the incidence of pre-cancerous colon polyps in Vioxx users. Preliminary data had shown that Vioxx might decrease the number of polyps, but Vioxx users had 3.9 times the number of heart attacks and strokes, and the study was stopped early because of safety concerns. Since receiving FDA approval in 1999, more than 80 million people used Vioxx before it was removed from the market.

Vioxx is a nonsteroidal anti-inflammatory drug (NSAID), like ibuprofen or Aspirin. NSAIDs are great drugs. They relieve the pain of arthritis; they reduce the fever of colds and flu; they provide great post-operative pain relief. But the older NSAIDs had a problem: Up to 20 percent of NSAID users develop stomach or duodenal ulcers, and this can lead to the serious complication of bleeding ulcers or stomach perforation.

So the drug companies developed NSAIDs like Vioxx which didn’t have the bad gastrointestinal side effects. Studies showed they were no more effective than the old NSAIDs for the treatment of arthritis, for example, but they were kinder to the stomach.

The initial study used to gain FDA approval was not designed to see if there were any bad cardiovascular effects of Vioxx, but some disturbing trends emerged. Yet it was not until February 2001, that an FDA committee met to discuss concerns about such side effects. Researchers from the Cleveland Clinic reviewed the data from the meeting that were publicly available and published an analysis on the data available on Vioxx and Celebrex in August of that year. They concluded that, “it is mandatory to conduct a trial specifically [looking at the] cardiovascular risks and benefits of these agents.”

The study was never done. The FDA had the authority to mandate such a trial, but it never took the step. Merck responded to the challenge by publishing numerous papers in the peer-reviewed medical literature by Merck employees and their consultants “confirming the favorable cardiovascular safety of Vioxx.”

Of course, I suppose asking Merck to weigh in against their own financial self-interest is a bit like asking the wolf pack to look out for the well-being of the sheep. On Nov. 1, one month after Merck withdrew Vioxx, the Wall Street Journal reported that internal e-mails, marketing documents and interviews with outside scientists who questioned the safety of Vioxx indicated that Merck was aware of the concerns about Vioxx, but chose to disregard, and even hide, the communications to protect sales.

What about the FDA, whose job it is to protect us? The FDA faces a true conundrum: The push to get effective drugs into the marketplace, and the responsibility to protect the public health. If we waited for proof that all FDA approved drugs were absolutely safe, with no adverse effects, then we would get no new drugs. If we waited for all the data on a drug, looking at every possible bad effect, then drug release would be so delayed as to be effectively stopped. No drug will ever be 100 percent safe. Its benefits must be weighed against the risks. But in the case of Vioxx, there are other, safer drugs available. Post marketing surveillance is imperative, and this is where the FDA dropped the ball.

The FDA’s job is not only to get drugs on the market, it is to protect the public health once they are out there. Big Pharma may not like watchdogs and regulation, but we little guys depend on those puppies!

Note: Celebrex has not been implicated in the increased risk of heart attacks and stroke.