Article on Phase II failure problems:
Interesting analysis of Phase II failure increases in the WSJ today . Sorry, I don't have the link.
FOLLOW THE MONEY
By SCOTT HENSLEY
Early Clinical Trials the Culprit
In Drug Development Slowdown
Always a game of long shots, drug research is now suffering from more-frequent failures during early clinical tests of new drugs. The pattern has implications for drug makers, investors and patients, as it threatens companies' efforts to replenish their pipelines.
The snags are surfacing during Phase II studies, or tests to determine if experimental drugs work well enough in humans to merit the large and expensive clinical trials mounted to prove their safety and effectiveness to regulators. The growing recognition of this bottleneck is prompting pharmaceutical companies to rethink their approach to drug development.
"It's a disaster," said Robert Ruffolo, president of research and development at drug maker Wyeth, in Madison, N.J. at a conference of pharmaceutical and biotech executives on strategic alliances held by Windhover Information in New York early this week. "We have a big problem that's getting worse."
Conventional wisdom within the industry has held that the roots of the current slowdown in drug development lie in earlier stages of research. A flood of information unleashed by the decoding of the human genome, this argument goes, has made scientists' work paradoxically harder and costlier by inundating them with more potential targets for research than they can handle.
But the real culprit in the deepening slowdown now appears to be Phase II studies -- the clinical tests that drug makers rely upon to determine if the science behind a potential drug is valid. Industry wide, success rates in these proof-of-concept trials have fallen to 25% from 40% in just five years, according to Dr. Ruffolo. Simultaneously, the time these studies take to reach an answer, positive or negative, has doubled to almost three years since 2000, Dr. Ruffolo said.
These are big changes from historical norms, and they're upsetting drug companies' carefully calculated business models to restock the world's medicine chest with new products. "R&D productivity is declining. People who say it's not aren't willing to accept reality," Dr. Ruffolo said.
The main reasons for the slowdown stem from traditional bugaboos: safety issues, disappointing effectiveness and regulatory concerns. But the hurdles in all these areas are higher than they used to be, he said, as standards have increased on all fronts. An emphasis on finding novel drugs, rather than me-too medicines in a well-understood class, has compounded the difficulties for drug developers. "Novelty carries a greater risk of failure," Dr. Ruffolo said.
Though the rise in failures during Phase II is sobering, early termination of ill-fated drugs is cheaper than seeing drug candidates flame out in final clinical testing called Phase III. But even those savings may be disappearing. A growing number of studies in Phase II, especially a subset of late-stage studies sometimes referred to as Phase IIb, are becoming so large that they rival the size and expense of pivotal Phase III studies conducted just a few years ago. And the fall in productivity has dashed hopes, for now anyway, that historical success rates in research might increase as scientists gained more insights into disease.
The Phase II bottleneck complicates Big Pharma's efforts to find drugs quickly to replace those losing patent protection. Soon after arriving at Wyeth in 2000, Dr. Ruffolo committed to submit at least two new drugs every year for Food and Drug Administration approval by the second half of this decade. The Phase II problem is throwing off his previous calculations on how he'll get the job done, he said. Now, he's called on his scientists to put 12 products a year into Phase II instead of eight. He's also stepping up efforts to license more early-stage experimental compounds to supplement in-house research.
This year, Wyeth submitted a novel contraceptive for FDA review, and by year-end the company expects to submit a new antidepressant as well. Meanwhile, Dr. Ruffolo's pushing for more efficient Phase II studies. "Just because there's a problem doesn't mean it can't be fixed," he says. One initiative involves the creation of five centers around the world specializing in early clinical development to cut the time it takes to run Phase II tests.
Another tack towards research improvement involves blurring the lines between the "R" and "D" of research and development -- the basic science of drug research versus drug development through human testing. Researchers at Novartis AG, Basel, Switzerland, are attempting to map a dozen or so molecular pathways common to many diseases as a way to sort through biological complexity. With these maps in hand, a drug that works in a few patients with rare diseases, for example, may prove helpful in a range of conditions.
By carefully picking the right patients for these early exploratory tests, the Novartis researchers hope to get definitive answers about their experimental drugs earlier, reducing the time to develop the medicines. "We expose the flaw of these programs very rapidly," Trevor Mundel, head of exploratory clinical development at Novartis, told the audience at the Windhover meeting. "We don't get stuck in three-year Phase II studies."
The company recently tested a drug in four patients suffering from a rare disorder that leads to rashes when exposed to environmental stress, such as cold. In a matter of hours, the drug eliminated telltale rashes in one patient, showing the medicine could block an inflammatory factor in the immune-system that is also involved in diseases ranging from asthma to rheumatoid arthritis. The other patients responded within days. With the concept validated, Novartis decided to continue development of the compound. Without the early positive result, Dr. Mundel said, Novartis would likely have discontinued the program.
Drug researchers are used to failures, but the recent problems in Phase II represent a new challenge. Efforts like these at least try to restore the odds of the game.
