Healthy Skepticism Library item: 161

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Publication type: news

Rowland C.
Drug makers revamping clinical-trial system: New test strategies focus on weeding out duds sooner
The Boston Globe 2004 Dec 21

Full text:

Faced with weak development pipelines that are putting a drag on stock prices, drug manufacturers are retooling the decades-old system of clinical trials to make it faster and cheaper.

The initiatives represent a revolutionary overhaul. The current clinical-trial system has been the gold standard of American drug development for 40 years. But it is producing fewer and fewer drugs, and drug companies that once had a strong selection of brand-name drugs in their cupboards are contemplating a bleak future.

‘‘The industry has been in the doldrums for a while,” said Herman Saftlas, senior healthcare analyst at Standard & Poor’s. ‘‘We’re talking about companies that have just one or two products they are looking at in terms of growth.”

In the most widely adopted move, drug companies are combining their earliest safety and dosing tests in humans with an examination of the drug’s effectiveness. Manufacturers also want to use ‘‘biomarkers” instead of patient health to determine whether a compound works in the body. And they are beginning to use genetic profiles to select clinical trial subjects who are most likely to respond favorably.

The idea is to weed out potential duds as quickly as possible and increase the likelihood of success as promising drugs move out of the laboratory and into human subjects.

The initiatives, which are the subject of a number of discussions within the FDA, are ongoing at a time of widespread public debate over safety, high drug prices, and the costs of research and development, which Tufts University has estimated at $800 million for every successful drug.

‘‘Business as usual is no longer going to be possible,” said Sandro Aruffo, president of the Abbott Bioresearch Center in Worcester, a division of Abbott Laboratories. ‘‘If we target our dollars more effectively to those targets that are really likely to yield new medicines, the better off we are going to be.”

Abbott scientists in Worcester plan to combine safety tests on the compound, ABT325, with tests of its effectiveness. If blood tests show that ABT325 fails to disable a key protein associated with lupus, Abbott can flush the drug from its development pipeline early and save hundreds of millions of dollars that would be wasted in later-stage trials.

The initiatives stem from a recognition in the last two years that the old clinical-trial model is producing too few new drugs, said Christopher-Paul Milne, research director at the Tufts Center for the Study of Drug Development, an academic institute that receives drug company funding in Boston. In 2002, drug companies applied for approval of just 22 new drug molecules, about half the number of approvals sought during the 1990s, he said.

‘‘They’re saying let’s redesign the process of clinical trials to make it more streamlined and efficient,” Milne said.

Yet the problems with using the new approaches became evident last week, when AstraZeneca Pharmaceuticals LLC disclosed that its anticancer drug, Iressa, did not extend the lives of cancer patients. The FDA gave Iressa a fast-track review and approved it in 2003 based on preliminary evidence that it shrank tumors in just 10 percent of patients. Follow-up studies showed that did not translate to better survival.

Traditionally, if a drug has shown promise in mice and rats, drug companies launch phase 1 safety trials in humans, followed by phase 2effectiveness trials that measure clinical outcomes in patients, followed by the most-expensive phase 3 ‘‘double-blind” trials that compare hundreds or thousands of patients taking the drug to large numbers taking a placebo.

The Food and Drug Administration has added requests for so-called phase 4, post-market reviews of a drug once it is being prescribed and taken by hundreds of thousands of patients. But the Food and Drug Administration has been criticized by members of Congress for failing to effectively monitor the progress of those reviews. The FDA said in 2003 that 60 percent of 1,339 phase 4 post-approval monitoring studies it requested had not even begun.

The issue of safety once a drug reaches market reached a crisis in the last few months because of health problems stemming from widely used drugs that generate billions of dollars for their manufacturers. Merck & Co., withdrew its arthritis pain reliever Vioxx, approved for use in 1999, after spending years fending off questions about its potential risk to cardiovascular health. Pfizer Inc. last week said it’s drug in the same class, Celebrex, showed increased cardiovascular risk in a high-dose clinical trial for colon cancer. Pfizer said it would not withdraw its drug from the market.

Instead of correcting its record on post-market safety reviews, however, the industry is more clearly focused on innovative strategies to improve clinical-trial success. The moves are occurring throughout the industry, including at big companies like Pfizer and Novartis AG.

‘‘We’ve embraced it with enthusiasm,” said Dr. Mark Fishman, head of global research for Novartis, the Swiss company that moved its drug discovery laboratories to Cambridge in 2003.

They are taking advantage of the phase 1 safety trials — the first time an experimental drug is put into a human body — to also measure its potential to fight disease. The new tests are fast. Instead of waiting to measure clinical outcomes — to see if someone gets better — these early checks measure things like the presence of a specific protein in the blood of a trial subject, or a change in an enzyme associated with tumor growth.

A potential downside to weeding the pipeline earlier is that worthy compounds may be discarded by drug company scientists prematurely, before teaching hospital clinicians have a chance to study its effects, said an experienced clinical investigator, Dr. Steven C. Schachter, an associate professor of neurology at Harvard Medical School and physician at Beth Israel Deaconess Medical Center. A physician performing research in a given area may recognize benefits in full phase 2 or phase 3 trials that would not be apparent to drug companies, which often perform phase 1 safety trials at their own clinics.

‘‘My concern with this approach is it might lead to discontinuing development of a drug that could conceivably have beneficial effects other than the ones being looked at,” Schachter said.

The FDA said the trend toward combined safety and effectiveness reviews at phase 1 does not present regulatory issues if the time patients are exposed to experimental compounds remains the same.

‘‘As long as the exposure of patients isn’t longer than it was before, it is not a problem for us,” said Dr. Robert Temple, director of the FDA’s Office of Medical Policy. The trend, he said, is being driven by sound science:
‘‘The number of things to measure — things in blood, things in cells, DNA turned on or off — is just hugely growing.”