Drug tests: too speedy - or safe enough?

Once extremely cautious, government regulators now look to approve as speedily as possible medicines whose benefits exceed their risks. Did Vioxx fit the bill?

Prescription drugs pulled from the market. Drug ads voluntarily yanked from TV and print. "Black box" warning labels placed on some medicines, and safety doubts raised about others.

As Americans try to figure out how suspect drugs got into their medicine cabinets - and who is to blame - two startling facts are coming to the fore: 1) The consumption of all medications involves some risk and 2) The bar for establishing their safety is set much lower than many people think. Furthermore, some experts say, these risks are almost impossible to avoid.

"People need to understand that all drugs by definition are poisons and need to be used appropriately and selectively where you anticipate the benefit to exceed the risk," says Steven Weisman, a pharmacologist at Innovative Science Solutions in Morristown, N.J., and a consultant to drug companies conducting clinical trials.

The seeds of the current crisis were planted more than a decade ago when Congress, under public pressure, directed the federal Food and Drug Administration (FDA) to make speedy approval of new drugs, rather than safety testing, its priority.

"It's a common misperception that the FDA approves drugs that are safe and effective," says Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development, a nonprofit research group affiliated with Tufts University in Boston. "The FDA actually approves drugs where the expected benefits outweigh the expected risks of that drug. It's always a risk-benefit analysis."

In the 1970s and '80s, the FDA had an "overly cautious approach to drug approval," in the view of Dr. Kaitin. Research by his center at Tufts showed the United States trailed behind other countries in developing new drugs, a so-called "drug lag."

The AIDS epidemic of the late '80s helped stir public thought to demand rapid drug development, he says, and Congress responded by giving the FDA new latitude to speed up the process, including fast-track approvals.

Today no new epidemic is causing a widespread public outcry so the pendulum has swung back toward safety concerns, Kaitin says.

"You can't have it both ways," says Mr. Weisman. That means choosing between a long approval process or bringing valuable new drugs quickly to the market, he adds.

Responding to criticism, acting FDA commissioner Lester Crawford asked the respected Institute of Medicine (IOM) in November to report back with recommendations on how the FDA could better detect dangerous side effects of drugs both before and after they reach the market.

Political solution?

But even before the IOM can report, Congress may take action. Sen. Charles Grassley (R) of Iowa, chairman of the Senate Finance Committee, held hearings this fall on dangers of certain drugs and plans to continue them in the new session. He also plans to introduce bills that would create an independent office of drug safety and require drug companies to register the results of all their clinical trials in a public database. Last week the British Medical Journal printed an article alleging that Eli Lilly and Co. knew that its antidepressant drug Prozac had "troubling side effects" as early as the 1980s and failed to publish the information. A group of editors of leading medical journals has said their publications will no longer accept articles about drugs unless all of their clinical trials have been publicly published.

Critics of the safety of the drug-approval system are advocating these and other reforms, including a ban or at least tougher limits on direct-to-consumer advertising.

But even they agree that it would be difficult to change the current system of clinical trials to ensure that every drug that reaches the marketplace is absolutely safe and has no dangerous side effects.

Even Phase III clinical trials, which usually involve several hundred to 3,000 volunteer subjects, are unlikely to reveal every adverse effect. That's because they still don't represent the vast differences among potential users. People may be taking combinations of other drugs that will react unfavorably, or have differences of age, gender, race, or even genetic ability to absorb drugs that the trials simply won't reveal. They also may take the drug in an incorrect dosage or for a longer period of time than is recommended.

There are "lots of unknowns until any drug is in the real world for some time," says Eric Topol, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

One example is Vioxx. The arthritis drug was allowed onto the market despite what Dr. Topol says were strong clinical indications of safety problems that should have prompted additional testing. In September Merck, the maker of Vioxx, voluntarily removed it from pharmacy shelves after some studies showed it increased the risk of heart disease. Vioxx quickly became popular in part because of heavy direct-to-consumer advertising. It's a prime example, Topol says, of why government should impose a moratorium of a year or two on advertising of new drugs so that their side effects can be monitored before they are widely used.

Others argue for deeper reforms. Currently, drug companies pay for and conduct their own clinical trials and then submit them as evidence to the FDA. Instead, the FDA should design the clinical trials itself and then contract with independent researchers to perform them, says Merrill Goozner, director of the Integrity in Science project at the Center for Science in the Public Interest, a consumer advocacy group in Washington. Then "we'll get objective information about drugs."

Though it would mean allocating more money to the FDA, the cost would be more than made up by lower-priced drugs, since the manufacturers would no longer pass the cost of their tests onto consumers, he argues. Many tests are aimed at expanding the market for a drug - searching for new diseases it can treat or new classes of patients - rather than safety, Mr. Goozner says. The FDA could eliminate those tests.

Both critics and defenders of the current system agree that the industry needs better so-called Phase IV testing - the continued surveillance of drugs after they are on the market.

Drug approval shouldn't be "a one-shot thing, the way it's been all these years," Topol says. "We need to change our mind-set." European countries require a five-year mandatory review of all drugs. "One could argue that five years is too long," he says. "There should be a continuous review, especially in the first year or two."

This area is where the FDA is criticized the most, Kaitin says. "I think the FDA will respond to that."

Independent scrutiny

Topol also sees an independent office of drug safety as vital. The FDA has good people, he says, but allowing those who are involved in bringing a drug through clinical trials as quickly as possible to judge safety as well creates an intellectual conflict. "You're much less likely to criticize a drug in the post-approval phase," he says. "And that's why you need an independent group to monitor that doesn't report to the same people."

The public needs accurate information to keep from becoming discouraged and deciding that all drugs are equally bad and that consumers are powerless to do anything about it, Goozner says. Medical reporting that trumpets "hype and hope" headlines only adds to the hype already found in consumer advertising, says the former reporter for the Chicago Tribune.

When Vioxx and other so-called COX-2 inhibitor drugs, now under scrutiny for possibly causing heart problems, first arrived on the market, a major magazine cover story called them "super aspirins," Goozner says, "even though the pain relief was known to be no different" from that of earlier drugs.

Medicated nations

• Thirteen large drug-buying nations spent $341.9 billion on retail medication in the 12 months ending last October. The United States alone accounted for half of that total.

• The US also spent the most per capita ($590.72) compared with Japan ($440.34) and France ($343.42). Brazil spent the least ($26.43).

• The world's bestselling drug is Lipitor, used for high cholesterol. Its $10.3 billion in annual sales exceeds the yearly output of Rwanda's economy.

• Drug prices vary greatly even outside the US. South Africans spend 65 times the world price for amitriptyline, used to treat depression; Peruvians pay more than 40 times the market price.

Sources: IMS Health Inc.; US Census Bureau; World Health Organization

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