"Good science is part of good drug regulation," says the FDA's head of oncology, Richard Pazdur. AstraZeneca's Iressa may soon stand as a striking example of exactly what that means.
There is now new evidence that this drug works only in a subgroup of patients. What are the regulatory, clinical, and market implications of that finding? Has the slicing and dicing of blockbuster markets begun?
About one year ago, Iressa barely squeaked through the FDA approval process. Based on the trial data at that time, it was difficult to tell whether the lung cancer drug had any "clinically relevant" effect, Pazdur says. There were also troubling signs that the drug might have serious side effects. Iressa's approval was contentious, and the experience cast a shadow over the otherwise exciting field of targeted therapies.
Now, scientists have discovered a group of mutations in the EGFR receptor that explain a big part of this drug's activity. Patients who acquire one of these mutations do extremely well on Iressa. Unfortunately, the mutations are quite rare - only about 10 percent of patients show this response.
As Pazdur points out, the book is hardly closed on Iressa. The intriguing research documented in the recent Science and NEJM studies must be confirmed and further explored (see Mutations Hold Key to Lung Cancer Drug Function). But this news is already shaping the agency's thinking. "We will be asking people, especially those developing EGFR-targeting drugs, to look at this information," says Pazdur.
In a related story, in February the FDA approved DakoCytomation's EGFR-expression test just one week after approving Imclone's Erbitux (see Erbitux Redux, in Briefs). Erbitux is a different flavor of targeted therapy, since it uses an antibody that binds to the cell surface, whereas Iressa is a small molecule. Also, Imclone used the Dako test during the drug trials. But the two events demonstrate how quickly the playing field is changing.
For now, there is still too little information about how Iressa works for the agency to act upon. But the FDA is watching closely. "Targeted therapies offer an opportunity for the agency to be part of an evolving science," says Pazdur.
In the end, it may not be possible to cherry-pick those patients who should take the drug. Just because a targeted therapy works better in one subgroup does not necessarily mean other patients won't also benefit - they may just benefit less. That's the sticky part, where weighing benefits, risks, cost, and other complexities comes in.
This situation is just one example of the phase we are now entering. Several speakers at CHI's latest "Biomarkers" meetings (see Minor Groove, below) pointed out that the next four to five years would be confusing for targeted therapy developers. Companies have to hash out the challenging issues around biomarkers both in clinical trials and as diagnostics.
The FDA's Pazdur has some good advice for anyone daring into this zone of uncertainty. "We strongly encourage people to do good science," he says, "and we will work with them to make sure the right questions are asked."