In the new era of targeted therapies, is it time to rethink clinical trial design

Two cousins with cancer were randomized to different arms of a clinical trial of Roche’s melanoma drug, PLX4032. The implications were covered in a NYTs story, which questioned the ethical implications of our current trial design.

The central issue is whether a controlled trial for extending life is ethical. In this instance, PLX4032 was shown to shrink tumors in some patients, but only for a limited time, and the key question was whether those patients would live longer. The standard chemotherapy used in melanoma, dacarbazine, slowed tumor growth in 15% of patients for an average of 2 months, while the Roche drug halted tumor growth in 81% of patients for an average of 8 months.
As the article notes, some agents may be so much more effective than existing drugs that putting patients into control groups, and delaying access to thousands of others, is unfair. And many oncologists believed that if the Roche drug provided relief by shrinking tumors, patient lives would improve.

“With chemotherapy, you’re subjecting patients to a toxic treatment, and the response rates are much lower, so it’s important to answer ‘Are you really helping the patient?’ ” Charles Sawyers, who chairs human oncology at Sloan-Kettering, told the Times. “But with these drugs that have minimal side effects and dramatic response rates, where we understand the biology, I wonder, why do we have to be so rigorous? This could be one of those defining cases that says, ‘Look, our system has to change.’ ”

Roche was urged last year to seek accelerated approval. According to the Times article, getting patients to join a trial for a drug already on the market was unlikely, since the odds were only 50-50 that a patient would receive the med and patients were already clamoring for the Roche treatment. And without the trial, obtaining “definitive” effectiveness data was also unlikely. Yet the trial would cost $100 million and FDA approval may have to wait 2 years, which some docs felt was a waste when the important issue was prolonging remissions.