Published online 4 June 2007 | Nature | doi:10.1038/news070604-1

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The zero effect

Small quick trials may help shape the development of new drugs.

New drug trials could rule out poor drug candidates quickerNew drug trials could rule out poor drug candidates quickerPunchstock

New clinical-trial results offer not just a modicum of hope for some future cancer patients, but also encouragement for those looking at more efficient techniques for developing new drugs.

Yesterday, scientists from the US National Cancer Institute (NCI) said they had successfully tested a new drug — called ABT-888 — in six patients with various forms of advanced cancer. The drug was developed by Abbott Laboratories of Abbott Park, Illinois, and is designed to shut down the action of PARP, a protein that helps some cancer cells survive the body's calls for them to kill themselves.

Scientists tested ABT-888 in far fewer patients, and far earlier in its development, than is usual for new cancer drugs. The test was called a 'phase 0' test to distinguish it from so-called 'phase 1' trials, which are usually the first tests of new drugs in humans. The scientists said this is the first phase 0 trial ever conducted.

"This is an important proof of concept that these phase 0 trials can be done, and that they will expedite clinical trials for new agents," said the NCI's Shivaani Kummar, who led the trial and announced its findings at the annual meeting of the American Society of Clinical Oncology, in Chicago.

The idea of a phase 0 trial is to use small doses in a few patients to see whether the drug is hitting its intended target. The very small doses reflect the fact that phase 0 trials take place before the safety of the drug in humans has been demonstrated. Rather than look for clinical effects, such trials look for changes in 'biomarkers' — tell-tale molecules associated with the drug's proposed mechanism of action.

Proponents of phase 0 trials hope that by quickly ruling out drugs that have no effect on the mechanism that they are targeted against they can reduce the money lost testing drugs that turn out later to have no helpful effects. About 10% of drugs tested in people are eventually approved by the US Food and Drug Administration [Kola and Landis, Nature Reviews Drug Discovery 3 , 711-716 (2004); doi:10.1038/nrd1470, fs.html]">http://www.nature.com/nrd/journal/v3/n8/full/nrd1470fs.html, and the sooner the 90% that won't go the distance can be identified, the better.

Speedy results

The scientists who conducted the ABT-888 trial said it performed well on a biomarker test performed on samples from the patients' tumours and blood. Each patient in the study received one dose of the study drug. In all six patients in the trial, ABT-888 turned down the activity of its target protein by at least 95%, Kummar said.

Abbott is now planning phase 1 trials — which look at safety and dose tolerance — of ABT-888 given alongside established treatments. ABT-888 is designed to amplify the effect of these treatments, said James Doroshow, head of the NCI division that ran the phase 0 trial. If it proves safe, the company will move on to further trials looking for clinical benefits.

Kummar highlighted the speed with which the trial moved from concept to results. The NCI received approval to begin the study in December 2005, treated its first patient last June and delivered its first useful data in October, she said.

Skeptics have cast doubt on the idea that phase 0 trials will be useful. Doctors have tried and failed to use biomarkers in other areas of medicine to predict treatment success — for instance, in HIV. And drug companies have been lukewarm about phase 0 trials, unsure that they will eliminate very large amounts of time and money from the drug development process.

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Phase 0 trials also raise ethical issues. Patients receive such small amounts of the experimental drug that they have no chance of benefiting from the treatment.

But Kummar said that all the patients in the trial were informed that ABT-888 would not benefit them, and they chose to participate anyway. And, she said, this trial has already helped Abbott design its follow-up trials, which proves that the approach is useful. The NCI is already conducting a second phase 0 trial, using an imaging technique rather than biomarkers, and is planning a third.

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