Healthy Skepticism Library item: 1560

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Publication type: Journal Article

Tansey B.
Hard sell: How Marketing Drives the Pharmaceutical Industry: What FDA approval means: Agency weighs benefits, risks before drugs get to market
San Francisco Chronicle 2005 Mar 3;

Full text:

One in an occasional series.

The sudden halt to sales of the newly approved multiple sclerosis drug Tysabri this week, following alarms about the widely marketed painkillers Celebrex, Vioxx and Bextra, raises some tough questions about the U.S. drug safety system.

What exactly does it mean when a drug wins Food and Drug Administration approval? Isn’t it supposed to mean that the medication is absolutely safe? That the FDA knows all of its possible side effects? That it’s better than older drugs on the market? The answers are: No, no and no.

As much as patients would like to believe that FDA approval carries all those guarantees — and as often as TV drug commercials foster that impression of safety and superiority — the agency’s approval is much more provisional.

That doesn’t mean that an FDA approval is worthless, consumer advocates say. But patients also shouldn’t take it as an unconditional endorsement.

The FDA would be the first to say that drugs are approved based on knowledge that is not yet complete. It’s a point the agency has emphasized since the discovery of a fatal disorder in two Tysabri users, which led to the drug’s suspension Monday.

Drugs are approved based on several rounds of clinical trials, but those trials may not uncover all risks. Clinical trials usually include no more than a few thousand people taking the drug for a limited period of time. The ultimate test comes when the drug is released to the market to be used for longer periods.

“For any approved therapy, new and unexpected adverse events may occur that were not seen in clinical trials,’‘ the FDA said in a statement about Tysabri.

In addition, what drug industry officials and consumer advocates alike want patients to understand is that no one can declare any drug absolutely safe for all health conditions. Instead, drug approval is an act of deciding whether the curative powers of a medicine are valuable enough to justify exposing a specific class of patients to the possible side effects.

“When FDA evaluates safety, we look at the benefits outweighing the risks for the indication the product is being approved to treat,’‘ agency spokeswoman Kathleen Quinn said.

A drug with fairly severe side effects might be considered safe enough for patients with life-threatening conditions like cancer. But such risks would be unacceptable for a drug to treat the flu, for example.

How deeply the FDA should require manufacturers to delve for data on both risks and benefits before allowing a drug onto the market has long been a subject of controversy. Tysabri is just the latest focus of that debate.

Tysabri won fast-track approval in late November on the strength of a pair of clinical trials that were only halfway through their planned two-year course. The first year’s data, however, had already shown a significant benefit to patients with multiple sclerosis, slowing down the progressive decline that can lead to paralysis.

But two clinical trial subjects under treatment for more than two years have apparently developed a life-threatening central nervous system disorder, and one of them has died. Experts must decide whether Tysabri played a role in causing the rare illness. The two subjects were taking Tysabri along with an older multiple sclerosis drug, Avonex, made by the same manufacturer, Biogen- Idec of Cambridge, Mass. The rare disorder has not turned up so far in those taking Tysabri or Avonex alone.

In the meantime, 5,000 patients have received Tysabri injections in the three months since the drug’s approval. One FDA critic said it’s worth investigating whether Tysabri’s approval should have been accelerated.

“Was the medical need for this drug so serious, was its promise so promising, that it outweighed the need to take it through the normal clinical trial process?’‘ asked Merrill Goozner, author of “The $800 Million Pill: The Truth Behind the Cost of New Drugs.’‘

Consumer advocates who have been highly critical of the FDA’s handling of other drugs have not leaped to fault the agency’s early approval of Tysabri.

“It is always a delicate balancing act for the FDA to want to make good new drugs available quickly — especially if it is a true breakthrough product — versus waiting to collect all the possible data that one could want,’‘ said Dr. Jerry Avorn, a Harvard Medical School professor and author of the book “Powerful Medicines: the Benefits, Risks and Costs of Prescription Drugs.”

In general, Avorn said, unexpected risks can crop up once a drug comes into widespread use, even when the clinical trials that supported FDA approval were very thorough. Some side effects only appear in patients with health conditions not represented in the trial group, he said. Other adverse symptoms take years to develop. And some drugs cause damage only when used in combination with other medicines.

“The dirty underbelly of this is that the likelihood that some of these unexpected side effects will develop is greater if the pre-approval studies are too small, or too brief, or enroll patients who are much healthier than the patients who are going to be taking the drug in normal use,’‘ said Avorn, who favors longer studies on larger groups that are more representative of the real-world patient population.

Of greater concern in the eyes of critics like Avorn is the FDA’s system for detecting serious new risks that surface after a drug is approved, and its record for getting the products off the market or beefing up their warning labels.

The rare disorder among Tysabri users was picked up fairly soon after the drug’s release, as its manufacturers continued their clinical studies — a condition of fast-track approval. But the long period that elapsed before heart attack risks were confirmed for Vioxx, Celebrex and Bextra has spurred an intense re-examination of the FDA’s post-marketing surveillance of the safety of approved drugs.

Millions of patients continued to rely on the agency’s approval of the three painkillers after evidence surfaced in 2000 that the drugs could boost the risk of heart attacks and strokes. The FDA didn’t require definitive studies to nail down the extent of those risks, and discouraged its experts from speaking publicly about the danger. An FDA advisory panel recently found that all three drugs increase cardiovascular dangers, but concluded that the risks might be acceptable for a limited group of patients who don’t have good treatment alternatives.

In the middle of the controversy, the FDA asked for an outside evaluation of its drug surveillance program and undertook some safety reforms. This week, the agency told Congress it wants the power to strengthen drug warning labels unilaterally, without the need to negotiate with manufacturers.

Despite recent controversies over drugs pulled from the market, the industry’s major trade association maintains that overall, the FDA does a good job of detecting risks both before and after marketing of new drugs.

“About 3,000 brand-name drugs are on the market today, and in the vast majority of cases, they are safely and effectively treating patients,’‘ said Jeff Trewhitt, a spokesman for the Pharmaceutical Research and Manufacturers of America.

Some doctors, however, are concerned enough about undiscovered side effects that they advocate waiting to prescribe new drugs until they have been on the market for a few years.

Dr. Randall Stafford, an associate professor at Stanford University School of Medicine, points to a series of heavily prescribed drugs later shown to have surprising dangers, which included diabetes and cholesterol medications as well as Vioxx, Celebrex and Bextra.

Stafford is the co-author of an influential study showing that the three painkillers were widely prescribed to people who would have done just as well on older, cheaper drugs. And in hindsight, those patients would have avoided the cardiovascular risks that have now been confirmed. An FDA whistle-blower, Dr. David Graham, recently estimated that Vioxx alone caused up to 140,000 cases of coronary heart disease in the United States, many of them fatal.

“All these instances point to a need to be more conservative about new drugs,’‘ Stafford said.

But physicians often follow exactly the opposite prescribing pattern, Stafford said. Pharmaceutical firms heavily promote new drugs to achieve the widest possible usage in a short period after their introduction to the market.

“The drug industry has tended to focus on a strategy of developing blockbuster drugs,’‘ Stafford said. “It has to be used in ways that are beyond the boundaries of who we might want to use it — where the drug is most useful and cost-effective.’‘

Trewhitt, the industry spokesman, said the decision to hold off using new drugs for a few years should be left to doctors and patients. But he said both should be reassured by the FDA’s overall safety track record.

Patients should be aware, however, that the FDA’s approval of a new drug doesn’t necessarily mean that the drug is superior to drugs already on the market for the same condition, said Larry Sasich of the watchdog group Public Citizen.

Many new drugs are never studied in head-to-head competition with older products to see if they’re safer or more effective, Sasich said. Instead, drugs are often compared with a placebo in clinical trials.

“There’s a common belief that new equals better, and that’s not the case, ‘’ Sasich said. “Less-safe drugs do get on the market with the system as it is. ‘’

Harvard’s Avorn is one of the doctors who believes in waiting a year or more before prescribing a newly approved drug, unless it offers breakthrough benefits for a serious condition.

“It’s particularly tragic when somebody has a potentially lethal side effect for a drug that was no better than other drugs around for years,’‘ Avorn said.