Is phase III testing necessary for targeted cancer drugs with early and obvious benefit?

Generally, FDA-approved clinical trials progress through three phases: the first shows safety, the second determines efficacy and further evaluates safety, and the third seeks to prove a drug's superiority over existing treatments. But when a drug's benefit is obvious in the first or second phase, is the third, and costly, phase needed?

This question was recently poised by Robert C. Doebele, MD, PhD, of the University of Colorado Cancer Center in Denver in Nature Reviews Clinical Oncology (2013; doi:10.1038/nrclinonc.2013.135). He pointed out the example of the drug crizotinib, which is used to treat a subset of patients with lung cancer with a specific gene mutation known as the ALK-EML4 rearrangement (ALK+). For patients with ALK+, crizotinib can be extremely beneficial—both the phase I and phase II clinical trials of the drug showed dramatic response in the majority of treated patients with ALK+, even in those with advanced disease who had received prior chemotherapy. In light of these results, the FDA approved the drug in 2011.

But testing continued. Specifically, a phase III trial of crizotinib known as PROFILE 1007 screened 5,000 patients with lung cancer and randomly assigned 347 patients with ALK+ to treatment with crizotinib or chemotherapy. As everyone expected, crizotinib proved superior in the ALK+ subset, with a progression-free survival of 7.7 months on crizotinib compared with 3 months on chemotherapy, and an overall response rate of 65% on crizotinib compared with 20% for chemotherapy.

“The question is whether the phase III trial was needed at all,” said Doebele.

In addition to the continued testing that requires some patients to be randomly assigned to a treatment that most involved expect to be less effective, a phase III clinical test is hugely expensive. “This expense can deter some manufacturers from pursuing promising drugs,” Doebele said. For example, imagine if a strong candidate drug existed that targeted only 1% to 2% of patients with lung cancer – knowing the expense of a phase III clinical trial, a drug sponsor may be unlikely to push for approval because the small, eventual market may not justify the cost of testing.

Such is the case for the gene ROS1, which is mutated in 1% to 2% of lung cancers. In a phase I clinical trial, lung cancer patients positive for ROS1 fusion showed responses to crizotinib that are nearly identical to those of patients with ALK+. Doebele argued that with genetics showing similarities in the cancer-causing abilities of ALK+ and ROS1 and with phase I results for crizotinib in the treatment of ROS1 lung cancer so closely matching results in ALK+ lung cancer, the bar for drug approval should be lower. Perhaps a phase II or III trial of crizotinib for ROS1 lung cancer is unneeded?

Doebele acknowledged that changing the process would burden clinicians with monitoring a drug's long-term side effects. However, he explained that it would streamline the approval process and get the drugs available for patients who desperately need them.

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