trials we want to do, in which the biology, especially the mutations, drives the treatments tested in patients,” Comis said.

Capdeville agreed, noting that by the time a drug and companion diagnostic are approved, the field often has changed markedly, with newer genetic techniques coming to the fore. “Still, we have to start at some point when we do a clinical study, so we need informed consent that is written carefully to allow the flexibility to not only work with the assay you have at the start of the study, but to be open to some more exploratory work as better technology becomes available. It is critical that you have the ability to store samples for future testing,” he stressed.

Pazdur said that the label for a companion diagnostic merely states that it is FDA-approved. “Inherent in that is the belief that these tests will change over time and that’s why there will be bridging studies that are done that compare one in vitro diagnostic to another in vitro diagnostic. I don’t think anyone in the FDA believes that this is a static field. The grand daddy of in vitro diagnostics is estrogen and progesterone receptor testing, and that has evolved since the mid-1970s due to various bridging studies that compared different technologies,” Pazdur said.

But Mendelsohn responded that there is a lag in implementing improvements to companion diagnostic tests because the assays are paired to specific treatments. “When you check for KRAS, you have to use the approved paired assay, which we all know misses some mutations in KRAS, if you want to get paid for giving the drug. So, your philosophy hasn’t hit the practice of medicine yet, unfortunately,” he said.

Regulatory Oversight for Trials of Small Subsets of Cancer Patients

Participants discussed the appropriate regulatory oversight for trials of small subsets of cancer patients. Pazdur noted that “when there’s a very small population of patients that could benefit from a drug, it would be nearly impossible to conduct a randomized study. Instead, we would take a look at the response rate and the toxicities of the drug,” and if the benefits outweigh the risks, the drug would be approved for the indication, he said.

Pazdur added that “one has to balance out what you’re seeing in this small subgroup vs. what you’re seeing with existing therapies. If you have a drug that has an exceedingly high response rate, we would take a very kind look at that, and proceed with an accelerated approval for that indication. For rare diseases in general we have taken a very liberal policy, even when it



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