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What's the Matter with Clinical Trials?

One of the biggest moments at the annual meeting of the American Society of Clinical Oncology last month came when a drug investigator from M.D. Anderson Cancer Center presented explained that a recent clinical trial for the drug Avastin had left doctors "with no more clarity" about how to treat brain cancer patients than they had before the trial, according to the New York Times.

The randomized, controlled trial had worked, Clifton Leaf writes. It had done what science is supposed to do, even though it found "no difference in survival between those who were given Avastin and those who received a placebo."

Leaf says this moment slices to the core of what is wrong with clinical trials in the US. After around 400 completed clinical trials, it is still unclear why Avastin does or does not work in certain patients.

Genetic variation is the difference for this confusion, and it is likely at the core of many other problems that confront drug developers, Leaf explains noting: "Researchers are coming to understand just how individualized human physiology and human pathology really are. On a genetic level, the tumors in one person with pancreatic cancer almost surely won’t be identical to those of any other."

“Despite looking at hundreds of potential predictive biomarkers, we do not currently have a way to predict who is most likely to respond to Avastin and who is not,” spokesperson for Genentech, a division of the Swiss pharmaceutical giant Roche, told the Times.

The biases that pharmaceutical firms on the hunt for the next blockbuster bring into their trials is certainly one part of the reason why so many expensive trials fail, or are inconclusive.

But there is a fundamental problem "with the nature of clinical trials themselves," Leaf writes, explaining that although roughly 53 percent of new cancer diagnoses are in patients who are over 65, that group accounts for just 33 percent of participants in cancer drug trials.

But even if the demographics of study groups could be better matched to the likely recipients of the drugs, no group of volunteers could match the biological diversity of the eventual consumers.

Looking at disease subtypes is certainly one place to start to fix the system. In cases where disease subtypes are already known, such as in the case of Genentech's breast cancer drug Herceptin, "it may be feasible to design small clinical trials and enroll only those who have the appropriate genetic or molecular signature," Leaf suggests. He points out that 60 percent of the drugs in development at Genentech/Roche are being developed with companion diagnostics to identify the optimal patients.

But this "piecemeal approach is bound to be slow and arduous," Leaf says, adding that "we'd be far better off changing the trials themselves.

The solution may be in a model that the Biomarkers Consortium, an effort led by NIH, FDA, pharma firms, and other partners, has launched - the I-SPY-2 trial, he suggests.

The goal of this effort is to find out whether neoadjuvant therapy for breast cancer reduces disease recurrence, and which drugs work best. The project partners are testing up to a dozen drugs from multiple companies and they phase out the ones that do not appear to work without stopping the study.

The Biomarkers Consortium model enables researchers to learn-as-they-go during the trial, and to incorporate new knowledge into the ongoing trial, Leaf says.