As Pfizer Inc. tries to digest yet another monster merger, it's taking great pains to convince the world this one is different. Since unveiling in January the cash-and-stock deal for Wyeth, worth $68 billion at the time, Pfizer has updated its pipeline and promised top jobs to key Wyeth executives. The message: We're a new Pfizer, with new blood, better productivity and less bureaucracy.

But old and justifiable skepticism about big drug mergers overshadows the upbeat message. A study from 2003 showed the top companies formed by megamergers of the previous 10 years lost on average 3% of their market share and production of truly innovative new drugs also fell. Meanwhile, top firms that avoided megamergers gained 10% market share.

A regulatory bottleneck from safety fears made a bad situation worse this decade. In 2007, the number of new drugs approved by the Food and Drug Administration hit a low not seen since 1983. Last year was better but not by much, especially in light of the industry's R&D budgets.

Pfizer's massive deals in 2000 (Warner-Lambert Pharmaceutical Co.) and 2003 (Pharmacia Corp.) brought the firm such blockbusters as cholesterol fighter Lipitor, the world's best-selling drug, and arthritis pain drug Celebrex. Lipitor and its $12.5 billion in sales last year accounts for nearly a quarter of Pfizer revenue.

Celebrex contributes more than $2 billion a year despite being part of the drug class (Cox-2 inhibitors) that includes the infamous Vioxx and Pfizer's own Bextra, both now off the market.

The firm has known for years that Lipitor's patent expiration in 2011 would blow a hole in its balance sheet. Its attempt to develop a replacement, named torcetrapib, crashed in late 2006. News of the Phase 3 failure came only days after then-new CEO Jeffrey Kindler hailed torcetrapib as "one of the most important compounds of our generation." Last year, Pfizer said it would end research on cardiovascular treatments and several other areas.

Kindler also insisted for quite some time that Pfizer wouldn't go for the quick fix of another megamerger, but adding the top-line revenue of Wyeth, whose CEO is Bernard Poussot, was too tempting. Last year, the two firms registered $71 billion in sales. They also combined 130,000 employees, and a good portion will lose their jobs. The firm has already announced $4 billion in annual cuts for three years after the deal closes.

Now that the deal is under way and probably inevitable, Pfizer is downplaying the revenue and cost-cutting and talking up the new bipartite R&D structure: one group focused on traditional "small molecule" drugs, run by Pfizer's head of R&D, Martin Mackay, and the other on biotech "large molecule" drugs and vaccines, run by Wyeth's research director, Mikael Dolsten. Beneath them will work a series of research teams headed by "chief scientific officers." Wyeth's head of vaccine research, Emilio Emini, will run the new vaccine group, and the company's head of discovery, Menelas Pangalos, will run the neuroscience group.

Pfizer officials and representatives would not discuss the issue with The Deal, but in an audio interview posted April 9 on Windhover Information Inc.'s "In Vivo" blog, Mackay and Dolsten avoided the sticky details of how the massive R&D structure will also manage to be more nimble and productive. "None of us gets too excited about structures or models," said Mackay. "The key to success [is] human things, like how we work together and do we have an aligned philosophy and how we'll manage it day to day."

Mackay cited Pfizer's 18-month-old effort to build a network of biotech research centers as evidence of a new spirit of independence. "If you visited Rinat or CovX, you'd still feel you were in a biotech," he said, citing companies Pfizer has bought and added to the network. Among former Pfizer officials contacted for this article, the most charitable attitude was "wait and see," though it must be said many left after Kindler cleaned house. None would be named.

Perhaps the best way to sum up industry skepticism comes from Vertex Pharmaceuticals Inc. scientist Derek Lowe, who chronicles everything from dangerous chemistry to industry strategy on his blog, "In the Pipeline."

"There is no way, as far as I can imagine, to integrate ten billion dollars' worth of R&D in an orderly fashion," he wrote recently. "The best that they can hope for is 'not as hideous as the last couple of times,' but I suppose the lawyers wouldn't sign off on that language as appropriate."