By Tony Pugh and Seth Borenstein
Knight Ridder Newspapers
12-28-4
WASHINGTON -- For years, the pharmaceutical industry railed that the nation's regulators were too slow in approving new drugs to combat disease. Those delays killed people, the manufacturers argued.
Twelve years after the Food and Drug Administration streamlined approvals, people are still getting sick and thousands are dying. But now, the culprits are the prescription drugs pushed onto the market in rapid-fire order by the FDA.
For years, the FDA's more deliberate pace of approving medicines helped enable Europeans to get the first shot at new drugs. If problems surfaced abroad, the FDA merely failed to approve the drug.
Now that trend is reversed. Most of the world's truly new drugs - those whose active ingredients have never been marketed elsewhere - show up first in the United States. And the consequences can be deadly.
Despite this danger, the U.S. government doesn't actively solicit data on what happens to patients who take newly approved drugs. In fact, the U.S. system that monitors the safety of drugs already on the market is slow to respond and unable to flag warning signs, such as the excess cardiac deaths that led to the withdrawal of Merck's painkiller Vioxx, and to the news last week that Pfizer's counterpart, Celebrex, might cause similar problems.
The system also failed to uncover heart problems with naproxen, a prescription painkiller also sold over the counter as Aleve. The National Institutes of Health announced Monday that an Alzheimer's prevention trial found that people taking Aleve had a 50 percent greater risk of heart attacks and strokes than those taking a placebo.
As prescription drug use continues to soar in America, the combination of more drug launches, more adverse reactions and a poor safety monitoring system means that U.S. patients are at greater peril from dangerous new drugs than a generation ago.
"We're the guinea pigs," said Marcus Reidenberg, a professor at Cornell University Medical School in New York.
FDA officials, while conceding that their monitoring system needs improvement, stressed the gains that come from approving drugs faster.
"Lives are saved and suffering is reduced in the U.S." because drugs for cancer, diabetes and other ailments are released here first, said Steve Galson, the FDA's acting director of the Center for Drug Evaluation and Research, which oversees drug safety.
He is reflecting a huge marketing shift over a generation: In 1983, only 3 percent of truly new drugs debuted in the United States. Most appeared first in Europe or Asia.
In 2003, the United States launched nearly 60 percent of the genuinely new drugs. Among drugs approved in the United States before Europe or Asia was Vioxx, which one FDA drug-safety expert told Congress may have caused as many as 55,000 deaths over five years.
In addition, although it's unclear how many people are hurt by drugs introduced in the United States, adverse reactions are increasing sharply. In 1992, just before Congress directed the FDA to speed up drug approvals, there was one report for every 16,300 prescriptions. The rate grew to one report for every 9,000 prescriptions in 2003, a Knight Ridder analysis found.
Many lawmakers, including Republicans, are critical of the FDA's performance. But not the Bush administration. On Sunday, the White House chief of staff, Andrew Card, said the FDA is doing a "spectacular job" of protecting U.S. patients.
The pressure for FDA reforms increased on Friday, when harmful effects were released on Celebrex and the attention deficit remedy Strattera. Both were introduced first in the United States: Celebrex in 1998, and Strattera in 2002.
Stressing the monitoring system today are new drugs appearing first in the United States, the world's launching pad for new drugs since in 1998.
Since then, Knight Ridder's analysis found, 72 percent of unique new drugs approved by the FDA were sold in the United States before they were sold in Europe. But Europe and especially Great Britain continue to track and evaluate the safety of new drugs more aggressively.
"You know their [monitoring] system would have picked up a problem earlier than ours," said former FDA Commissioner Donald Kennedy. "Because [Europeans] are better than us - way better."
Sometimes Europe's early action saved U.S. lives. Sertinodole, a schizophrenia drug made by Abbott Laboratories, was sold in Europe for more than two years before it was found to cause sudden cardiac death and withdrawn in December 1998. By then, Abbott had withdrawn its request for FDA approval.
The U.S. leadership in drug introductions may help explain why the number of adverse drug reports is soaring. The 357,392 bad reactions reported to the FDA in 2003 are more than double 1995's figure and more than four times higher than those reported in 1990.
The FDA's Galson said the increase may reflect the fact that more Americans now take prescription drugs. But adverse drug reactions are growing more than twice as fast as the number of prescriptions.
From 1994 to 2003, the number of bad drug reactions reported jumped 145 percent while the number of prescriptions filled increased 59 percent, Knight Ridder found.
The FDA estimates that about 390,000 adverse reactions will be reported this year. Yet the FDA cautions that the actual number is likely to be between 10 and 100 times greater because of underreporting.
The issue of drug reaction and monitoring is a simple case of numbers. Before the FDA approves a drug as safe for sale, it's tested on a few thousand people - enough to find big and obvious side effects.
But when drugs are used by millions of patients, rare side effects can show up, some with deadly consequences. That's partly what happened with Vioxx. "We launch into overuse of these drugs when we don't know their effects," said Brian Strom, a University of Pennsylvania drug expert.
That means consumers should be wary. "If you don't want to be a guinea pig, don't take them for the first couple of years after they've been approved," said Sean Hennessy, a University of Pennsylvania pharmacology professor.
Pat Peebles, 60, a retiree in McDavid, Fla., started taking Vioxx in 2001 for arthritis. She figured it was safe because the government approved it. But on Sept. 23, 2003, Peebles began to sweat profusely. She felt pain in her stomach, then fell to the floor. It took EMTs 45 minutes to revive her.
Peebles didn't know that Vioxx by 2001 was the No. 1 prescription drug problem in the FDA's reporting system.
Peebles, now wiser, said: "When [drug companies] come up with these new drugs and say the government approved it, I wonder if it's going to be safe down the road."
The emergence of the United States as the world's primary drug launching pad began with implementation of the Prescription Drug Fee User Act in 1993.
The law allowed drug companies to fund most of the FDA's costs for approving new drugs. In return, the FDA pledged to slash drug approval times.
Faster approval of HIV drugs - the legislation's goal - was the first result. But over time, the law also cut overall drug approval times by nearly 50 percent.
That prompted drug companies to shift initial drug reviews and launches to the United States rather than Europe and Japan, where drug review times underwent no such reductions.
"There's more money here, a bigger market, less price regulation than anywhere else in the world," said pharmacy professor Stephen Schondelmeyer of the University of Minnesota.
The FDA says it needs to have a robust post-approval program, but that's not what the agency has, according to Wayne Ray, a professor of preventive medicine at Vanderbilt University in Nashville, Tenn.
The system, he said, "is broken" and designed to be passive: So few doctors or patients submit adverse-reaction reports, and drug company submissions are so spotty, that the FDA's database is little more than a collection of anecdotes, Penn's Hennessy said.
In addition, most of the 300,000-plus adverse reaction reports that the FDA receives annually are on paper, Galson said.
"We shouldn't be relying on this 1950s system as our way of discovering adverse reactions," Strom said.
The Bush administration has, however, significantly increased the number of FDA personnel involved in post-approval drug safety surveillance. It's up to 103 this year, from 77 three years ago. That amounts to one FDA drug safety monitor for every 31 million prescriptions filed in the United States.
Lack of manpower is not a new problem. Twenty-five years ago next month, Congress' Joint Commission on Prescription Drug Use offered this as its top recommendation:
"A systematic and comprehensive system of post-marketing drug surveillance should be developed."
It still hasn't happened.
- Researcher Tish Wells contributed to this article.
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