The following editorial is a response to a USA Today Editorial Staff Opinion.
Amid the furor involving pain drugs, it may be of interest to ponder the theoretical problem of the Food and Drug Administration prematurely deciding to ban a drug whose benefits outweigh its risks. But we must confront the reality that during the past 10 years, there is overwhelming evidence that the FDA repeatedly delayed withdrawing many drugs long after clear, unequivocal evidence of risks that outweighed any demonstrable benefits.
The often-failed FDA strategy of “risk management,” a dangerous interim alternative to taking drugs off the market, has ensured that thousands of people were injured or killed after certain drugs should have been pulled.
A recent example is the diabetes drug Rezulin, first marketed in 1997. By that December, it was taken off the market in the United Kingdom because of liver damage, many cases having occurred in the United States.
In July 1998, Public Citizen petitioned the FDA to ban the drug, which, although lowering blood sugar by a different mechanism than earlier diabetes drugs, had no evidence of improved mortality or morbidity. By July 1998, there were 560 reported cases of liver damage, including 26 deaths.
After failed efforts at “risk management,” Rezulin was withdrawn from the market in January 2000, by which time there were hundreds of additional cases of liver damage and 63 deaths. Other belatedly banned drugs include the painkiller Duract, the blood-pressure drug Posicor and the cholesterol-lowering drug Baycol.
Decisions to approve or remove drugs must be based on adequate evidence of both benefits and risks. For Vioxx, Celebrex and Bextra – the three COX-2 inhibitor pain/arthritis drugs – at approval there was no evidence that they were more effective than older drugs.
Only Vioxx, now withdrawn because of a significant increase in heart attacks, proved to be less dangerous to the gastrointestinal tract than older drugs. Celebrex and Bextra did not. Although at approval there was no evidence of increased cardiac risk from Vioxx or Celebrex, less than a year later a 2001 study on Vioxx found it was five times more likely than naproxen (Aleve) to cause heart attacks, and a Celebrex study prompted FDA concerns about cardiac risks for that drug.
Removing Celebrex from the market will be a major step forward for public health. For naproxen, the evidence of its harm is preliminary at best, and it is unlikely to pose cardiac risks as high as those documented for Vioxx or Celebrex. There is no basis for removing it from the market.
Unique risks without unique benefits should always be the algorithm for removing drugs.
Sidney Wolfe is the director of Public Citizen’s Health Research Group and co-author of the new edition of Worst Pills, Best Pills. Public Citizen’s Web site, www.WorstPills.org, lists what it says are safer alternatives to 181 drugs.
“This is a very confusing situation,” a top Food and Drug Administration scientist, Sandra Kweder, said of the controversy over Celebrex and other popular pain relievers. If the FDA is confused, imagine the feelings of doctors and patients caught in the backlash.
The story so far: Celebrex, along with Vioxx and Bextra, were a new class of drugs that held great promise to relieve suffering from arthritis without causing the digestive discomfort and bleeding associated with older medications. They were heavily marketed, and sales reached billions of dollars.
Three months ago, a study confirmed fears that Vioxx increased the risk of heart attack and stroke. Now Vioxx is off the market, pulled by its manufacturer, and last Thursday the FDA urged doctors to limit prescriptions for Celebrex and Bextra.
The Vioxx debacle exposed a much larger danger: The FDA’s monitoring of new drugs is inept. Even after Vioxx was implicated in up to 40,000 deaths, the agency seemed to react only after one of its scientists, David Graham, turned whistleblower and told Congress that the FDA’s procedures guarantee that unsafe drugs remain on the market.
As we’ve noted previously, that problem needs to be addressed urgently. Drugs that show Vioxx-like dangers should be removed, or their use should be sharply restricted. But another danger is emerging: the risk that overreaction will make helpful drugs unavailable to seriously ill patients for whom significant risk is acceptable.
The consumer group Public Citizen, for instance, is urging that 181 drugs be taken off the market. Doing so, no doubt, would save some lives. It also would relegate many others to pain, disability and premature death.
Nearly half of Americans take at least one prescription drug, and rarely are the safety issues clear-cut.
Consider Celebrex. A study released earlier this month found that patients who received several times the typical dose had an increased risk of heart attack and stroke. Previous studies showed the opposite. Another new study found that Celebrex caused fewer heart problems than naproxen (sold over the counter as Aleve).
If Celebrex were pulled from the market, millions who’ve found relief from painful, disabling arthritis would have to switch to other medicines such as ibuprofen or naproxen. But those drugs cause severe gastrointestinal problems in some people, resulting in more than 16,000 deaths a year. Patients and doctors have to decide whether the potential cardiac risk outweighs the drug’s benefit.
Certainty about drugs is impossible because clinical trials before FDA approval involve only a few thousand patients. New risks, or benefits, can emerge once the drug is prescribed to millions. Vioxx, for example, was showing promise for preventing precancerous colon polyps.
Overreaction can cause harm by:
- Delaying new drug approvals. Some patient-advocacy groups worry that the FDA is slowing approval of new drugs for cancer and other deadly diseases. Marqibo, a pill to treat an aggressive cancer that kills at least half of all patients with it, was turned down for accelerated approval earlier this month. That caution may be appropriate, but there is another side: “The number of people who die because of delayed approval far exceeds the number hurt by unsafe drugs,” says Steven Walker of Abigail Alliance, a group that wants quicker access to new drugs.
- Distorting the level of risk. Clinical studies often contradict each other, and wide-ranging conclusions are drawn from small samples. In the recently reported link between naproxen and cardiac risk, fewer than 3% of the 2,500 elderly patients suffered heart attacks or strokes over three years, a relatively small number for that age group. “We’re being given flash results based on single trials that haven’t been properly analyzed,” says Michael Weber, associate dean of New York’s Downstate College of Medicine. “There may or may not be a safety problem. At this point, we don’t know.”
- Jeopardizing health. In October, the FDA ordered antidepressants to carry tough labels warning of increased suicidal behavior in children. Banning the drugs would have threatened the health of a million kids getting relief from the agony of depression. The suicide rate in 15 nations has dropped by one-third during the past 15 years since these drugs were introduced. The FDA was right to urge greater monitoring instead.
Make no mistake: The FDA is badly off-track. It’s not watching closely enough to see that the drugs it approves are safe as well as effective. But most often, the right solution will be to restrict a drug’s use, not to ban it.
Risk can be controlled.
It can’t be eliminated.