Two years of high-profile product pullouts, Congressional investigations, and dwindling pipelines point to big challenges for big pharma.

The retreat started with Merck yanking its multibillion-dollar blockbuster painkiller Vioxx in September 2004—followed by Pfizer’s move to pull Bextra in April, and then Celebrex after that. And as the withdrawals sent stock prices plummeting, the drug giants started talking about focusing on personalized drugs targeting an individual’s genetic makeup.

Does fresh interest in precision drugs mark the demise of the mass-market blockbuster model, and shift R&D focus onto sub-populations of individuals? “The era isn’t over, but it is moving towards an end,” says Garret A. Fitzgerald, professor of medicine at the University of Pennsylvania School of Medicine in Philadelphia. “It is impossibly naïve to think one or two doses should fit all. I suspect it will look as archaic a business model as high-cost airlines in five years or so.”

Personalized medicine may still be a decade or more away, but drug makers are increasingly using genetic and biochemical biomarkers as they push forward. And one intriguing irony of this drill-down trend is that the more pharmas develop precision drugs, the more they will start catering to the developing world—if only to widen the sales net for their more focused products.

Equally, pharmas will have to pay more attention to the developing world if they hope to understand the genetic basis for variable drug responses.

pharmas will have to pay more attention to the developing world if they hope to understand the genetic basis for variable drug responses.

Western Focus

Data is hard to pin down, but according to a 2002 report in The Lancet, a report the World Bank also cites, only 16 out of 1,393 new drugs marketed between 1975 and 1999 were registered for diseases that were more prevalent in the developing world than in the West. “It is known that even the most successful drug cures—optimally—only 40 percent of the target population,” says Govindarajan Padmanaban, a researcher at Bangalore’s Indian Institute of Science. Global drug firms, he asserts, will have to focus on sub-populations using the tools of pharmacogenomics.

The cost of developing a drug, depending on which research firm you talk to, typically runs anywhere from $700 million to $1 billion. But the economics of success get trickier in an era of pinpoint medications—and so, the thinking goes, a rich crop of genetically diverse patient groups from the developing world will become an integral part of the clinical testing rather than just remain a cost arbitrage. In other words, testing in the developing world becomes essential, not just the cheap option it started out as.

Over the years, pharmas focused on developing mass-market drugs for dispensing in limited doses. But the rise of pharmacogenomics, which digs down into hereditary responses to drugs, has widened the scope of individualized medicines—and researchers like Abdallah S. Daar and Peter Singer, from the Canadian Program on Genomics and Global Health at the University of Toronto, say regulation will play a significant role in pushing trends in this direction.

In 2000, GlaxoSmithKline voluntarily withdrew Lotronex, originally approved in the United States by the Food and Drug Administration, after reports of adverse reactions to the medication for irritable bowel syndrome. But then patient and physician groups succeeded in convincing the FDA to recertify the drug in 2002, arguing that it had proved remarkably effective. The regulator, in turn, required GlaxoSmithKline to study the relationship between adverse events and genetic profiles as part of its post-marketing commitment. Now, the company is looking for links between adverse reactions and specific genetic profiles.

Changed Disciplines

Despite the history of big returns on blockbuster drugs, it appears the model has reached a watershed, one being the slowdown in submissions for new drug approvals—down from 131 in 1996 to 113 in 2004.

Besides pointing to a new business model, the falling numbers also suggest that as fewer new drugs move through development, drug firms will be forced to re-examine blockbuster prospects to ensure that the chances of withdrawal are minimized further.

Whatever moves down the pipeline, deeper investigations into responses are needed, argues Penn’s Dr. Fitzgerald, and that calls for the drug industry to develop new skills. “We need a new discipline—translational medicine and therapeutics—to train a new cadre of investigators,” says Dr. Fitzgerald.

If he had his way, investigators would be trained to use both preclinical and clinical data much more efficiently and quantitatively. Devising ways to pool research data more coherently wouldn’t hurt either, he says. The spike in cardiovascular event risk in trials of colorectal cancer drug COX-2—leading to its suspension in December 2004—might have been avoided had findings from studies of basic mouse and human pharmacology, epidemiology, clinical trials, and the regulatory bodies not been kept segregated, or so it has been argued. “We need to integrate those types of expertise together with emerging technologies in order to find safer and more effective drugs,” says Dr. Fitzgerald.