By now it was supposed to be the first blockbuster drug of the biotechnology industry. But tens of thousands of heart patients across the nation will have to wait a while longer for a new drug that dissolves the blood clots that cause heart attacks.

Known as TPA, it was widely expected to be approved by the Food and Drug Administration by now. But recently the drug failed to pass muster with a key panel of advisors to the FDA.

The setback stunned patients, their physicians, heart researchers, TPA manufacturers -- and Wall Street.

After the FDA advisory panel decided against approval, the stock price of Genentech Inc., the principal manufacturer of TPA, plummented $11.50 to $36.75.

The Wall Street Journal has assailed the panel, calling it the "flat-earth committee" in an editorial earlier this month.

Dr. Eugene Braunwald, chief of medicine at Harvard's Beth Israel Hospital and at Brigham and Women's Hospital, who has conducted extensive research on TPA for the National Heart, Lung and Blood Institute, said simply: "This drug should be made available as soon as possible."

Now, FDA Commissioner Frank Young is faced with a tough decision: to approve TPA because of the wide support the drug has with patients and physicians; or to follow the recommendations of the expert panel and wait until more data becomes available.

Just why TPA was rejected by the panel is a matter of controversy. The members of the advisory committee concluded that there was not enough evidence to show that the drug actually reduced the death rate from heart attacks. The drug's supporters have claimed that they were hampered by turf battles within the FDA and by bureaucratic inefficiency.

Heart specialists expect that the FDA will eventually approve the drug, which is manufactured under the brand name Activase. But the panel's recommendation may delay approval from six months to a year. So far, Activase has been approved for use only in France, the Philippines and New Zealand.

TPA, which stands for tissue plasminogen activator, is naturally found in the human body in small amounts. But with the help of genetic-engineering techniques, scientists can modify certain animal cells to produce the substance in quantity.

Medical and commercial excitement over TPA has been building since 1985, when the heart institute announced it was halting a clinical trial of TPA prematurely because the new agent was clearly superior to the comparison drug in breaking up blood clots. The researchers believed it would be unethical to withhold the drug from the patients in the experiment who were not receiving it. Then a week later, an independent group of scientists in Europe reported similar findings on TPA that confirmed the heart institute's study.

The potential market for TPA is significant. According to Genentech, 750,000 heart attack patients a year in the United States alone could benefit from TPA's ability to dissolve clots in the coronary arteries. The drug has also helped patients who suffer from blood clots in the lungs and may be useful in treating clots in the deep veins of the legs. Genentech says that TPA could be useful to a total of 1.5 million patients in the United States, 1 million in Europe and 600,000 in Japan. So far, more than 4,000 patients have been tested with TPA in clinical trials around the world.

Central to the controversy over TPA was the question of whether or not dissolving blood clots actually helps a patient's chances of surviving a heart attack.

For years, the cardiology community has debated the role of blood clots in coronary arteries as a cause of heart attacks. Other possible causes have included a buildup of fatty deposits in the arteries, a rupture of a blood vessel near these fatty deposits, an increased demand in oxygen or a spasm in the heart, Braunwald said.

But during the past few years, medical opinion -- at least among some heart specialists -- has changed. The use of arteriography to monitor blood flow soon after a heart attack begins and the successes of TPA and other clot-dissolving drugs have convinced a number of leading cardiologists that breaking up blood clots is key to controlling heart attacks. "Restoring blood flow to the deprived portion of the heart is the name of the game," Braunwald said.

But not all heart specialists are persuaded. Members of the FDA advisory committee did not dispute that TPA is a potent clot dissolver. But many were skeptical that clots actually cause heart attacks or that dissolving clots prevents heart attacks because Genentech has not conducted human studies to look specifically at these issues.

In contrast, another clot-dissolving drug, streptokinase, has been found not only to break up clots effectively but also to reduce the risk of dying from heart attacks by 20 percent. The findings on streptokinase, which were reviewed by the FDA's expert panel the same day as TPA's, were based on two studies involving a total of 24,000 patients.

Unlike TPA, streptokinase is an enzyme that is naturally found in a strain of bacteria and is extracted. Streptokinase has been used for years to treat blood clots in the heart cavity during surgery. At the FDA panel meeting in May, members recommended its approval for another use -- to dissolve clots in coronary arteries. But streptokinase is considerably less potent than TPA.

At the meeting with the FDA panel, however, Genentech did not have any studies to show that TPA actually reduces a patient's chances of dying.

"The failure to establish a decrease in mortality doesn't mean there is none," noted Dr. Bert Sobel, chief cardiologist at Washington University Medical Center and a consultant to Genentech.

Still, the biotechnology company could offer only preliminary information from an ongoing study at Johns Hopkins Hospital in Baltimore that TPA helps heart function.

As Dr. Jeremy Ruskin, Massachusetts General Hospital cardiologist on the FDA panel, pointed out, dissolving clots is a desirable goal and probably explains why TPA would be effective in preventing deaths from heart attack. But, he said, "we don't know that. Those data are not available. TPA is very clearly an effective thrombolytic {clot dissolver}, and my gut feeling is it is an exciting drug . . . but with regard to any proven benefit, I think the data are not there."

There was also considerable confusion about the proper dosage levels. Genentech representatives said that 100 milligrams of TPA was appropriate but then mentioned that some patients had received 150 milligrams. In addition, the FDA review committee expressed concern over reports of serious bleeding in the brain in some patients.

At the end of the day-long meeting, eight of the 11 panel members voted not to recommend approval, one voted for approval and two abstained.The rejection of TPA by the FDA's advisory panel has raised questions about the whole drug approval process.

FDA officials concede that the agency never specifically asked Genentech to provide mortality data until shortly before the meeting. By then it was clearly too late to generate that kind of information.

Said Peter Drake, a stock analyst at Kidder Peabody who tracks TPA: "FDA changed the rules and the playing field in the eighth inning."

Drake and others contend that TPA was the victim of a regulatory turf battle between two branches of FDA -- the Office of Biologics and the Office of Drug Research and Review. But interviews with FDA staff suggest that the reason could simply stem from bureaucratic inefficiency.

The FDA is not saying publicly what data it will now require from Genentech, given "the sensitivities of the stock market," said Thomas Zuck of the biologics branch. So it is not clear when a final decision will be made on TPA.

Robert Kamen of Genetics Institute, a rival of Genentech in the TPA market, notes that the decision by the FDA advisory committee "gives competitors a time advantage. We gain whatever time Genentech loses," he said. "Before, Genentech had a 2 1/2-year time lead. Now, the gap could be narrowed by anywhere from six months to a year."

Several companies are already working furiously to improve TPA by modifying the molecule so it will be easier to administer in emergencies. The goal is to extend the half-life of TPA so it can be given to a patient in a single injection rather than intravenously for what is usually an hour and a half.

"There are so many interests in TPA," said Braunwald. "But the most important concern is the patient. I'm not saying TPA is the only way to achieve it {dissolving clots}, but it's a terrific way to do it."

Marjorie Sun writes for Science magazine.