Unlike most industries, Big Pharma can't milk its best-selling "branded" drugs forever. That's because drug patents expire after 17 years. Indeed, because the testing and approval process comes after the patent is filed, a company usually has only 10 to 12 years to reap a high price from its drug once it hits the market. After that, the generic drug industry takes it over, and drains most of the profit out of it.

As a matter of public policy, that's surely a good thing, but it doesn't help companies that are trying to generate ever-increasing profits. For them, there is constant pressure to replenish expiring blockbusters with even bigger and more profitable drugs.

To a number of the analysts I spoke to who follow Pfizer, like Mr. Scala, the company's problem is really pretty simple: it has a number of drugs that have either lost their patent protection or will soon - and it doesn't have anything coming on line, at least in the short term, that will take up the slack. Norvasc, for instance, will lose its patent protection this year. Most ominous of all, Lipitor is coming off patent in 2010. How is the company ever going to make up that $13 billion in revenue?

What's more, Pfizer was banking a great deal on a cholesterol drug it had developed called torcetrapib, the first drug aimed at raising the level of good cholesterol, rather than simply lowering cholesterol levels, the way Lipitor does. It would have been huge. But in early December, the company announced that it had ended its efforts to develop the drug after a clinical trial showed a higher-than-expected number of deaths. The loss of torcetrapib was a crushing blow.

But the patent expiration issue, while very real, is to my mind the symptom of something larger. The era of the blockbuster - and the blockbuster business model - may well be coming to an end. If you get away from Wall Street, it's not hard to find people who view things that way. "I don't think the model makes sense anymore," said the Harvard economist David Cutler.

"The blockbuster model does not work as a business anymore," said Roger Longman, a managing partner at Windhover Information, a health care consulting company.

There are lots of reasons for this. For one, as Pfizer discovered with the failure of torcetrapib, when you live by the blockbuster, you die by the blockbuster - companies simply need to become less reliant on a small handful of big moneymakers that will inevitably go away. "If you go the blockbuster route," said Dr. Una S. Ryan, the chief executive of a small biotech company, Avant Immunotherapeutics, "any setback is going to be catastrophic."

For another, the larger society has become much less tolerant of Big Pharma's tactics. There is a backlash against the kind of direct-to-consumer advertising that has propelled many drugs into blockbuster status. Doctors are less willing to spend time with drug company sales representatives.

The game-playing by many companies to extend the life of their patents is under attack by Congress and the Federal Trade Commission. The Food and Drug Administration is giving tougher scrutiny to drug applications - especially for drugs that are only marginally different from those already on the market.

And as health care costs continue to rise, managed care companies are looking to drugs - and drug companies - to save money. Look, for instance, at Lipitor, which is unlikely to have much more sales growth. Why? Part of the reason is that a competing drug, Merck's Zocor, lost its patent protection and is now available in generic form. Pfizer can argue, as it does, that Lipitor is superior to generic Zocor. But it is not that much better. So a number of managed care companies have begun switching patients to the generic version, thus saving millions of dollars.