Questions and Answers on Iressa's (gefitinib) New Labeling

1. What is the new labeling for Iressa?

The Food and Drug Administration (FDA) has approved new labeling for gefitinib (Iressa) that limits its use to patients with cancer who in the opinion of their treating physician, are currently benefiting, or have previously benefited, from Iressa treatment. In addition, AstraZeneca will distribute the drug under restrictions as part of the Iressa Access Program 2. Why is the FDA limiting the use of Iressa? The FDA is limiting the use of Iressa because recent clinical trials have not shown Iressa to benefit patients with cancer.

2. When was Iressa first approved?

Iressa was approved for marketing in May 2003 under FDA's accelerated approval regulations (21 CFR part 314, subpart H).

3. What are the accelerated approval regulations?

These regulations allow FDA to approve products that provide a meaningful therapeutic benefit over existing therapies for serious or life threatening illnesses on the basis of an effect on a surrogate endpoint that FDA has determined is reasonably likely to predict clinical benefit. Accelerated approval is granted on the condition that the manufacturer must continue testing the drug in clinical trials to demonstrate that the drug indeed provides clinical benefit to the patient. If the studies fail to demonstrate clinical benefit of the drug, or if the sponsor does not pursue the confirmatory studies with due diligence, the FDA may withdraw the product from the market more quickly than usual.

4. What is a surrogate endpoint?

A surrogate endpoint is a laboratory finding or physical sign that may not be a direct measurement of how a patient feels, functions, or survives, but is still considered reasonably likely to predict therapeutic benefit for the patient. In the case of Iressa, accelerated approval was based on demonstration of response measured by tumor shrinkage in approximately 10% of patients with non-small cell lung cancer who had already received standard treatments.

5. How was accelerated approval applied to Iressa?

Iressa was approved on the basis of a surrogate endpoint which was approximately a 10% tumor response rate (tumor shrinkage) in clinical studies in patients with advanced lung cancer. This tumor response suggested that the drug was reasonably likely to have a valuable effect on survival or symptoms.

6. Who can receive Iressa under the Iressa Access Program?

Prescriptions for Iressa will be limited the following patient populations:

• patients currently receiving and benefiting from Iressa;
• patients who have previously received and benefited from Iressa; and
• previously enrolled patients or new patients in non-Investigational New Drug Application (non-IND) clinical trials approved by an IRB (Institutional Review Board) prior to June 17, 2005.

7. Will any new patients be able to obtain Iressa?

New patients may be able to obtain Iressa under the Iressa Access Program if they are eligible to participate in a non-Investigational New Drug Application (non-IND) clinical trial approved by an IRB prior to June 17, 2005 (no new patients can be started after June 17, 2005). New patients may also qualify for enrollment in clinical trials for Iressa that are conducted under an IND.

8. What is an IND?

An Investigational New Drug (IND) application is a submission from a company that FDA uses to oversee clinical research and the use of investigational drugs involving patients.

9. What is the reason for the Iressa Access Program?

FDA has carefully reviewed data from the completed clinical studies of Iressa, including the confirmatory trial that was required by the agency as part of the drug's accelerated approval. The confirmatory trial enrolled patients with advanced non-small cell lung cancer (NSCLC) who had failed one or two prior chemotherapy regimens. In this large study, 1,692 patients were randomly assigned to receive either Iressa (gefitinib) or placebo. The results of the study showed no significant survival benefit for those patients treated with Iressa. Three other studies of Iressa in patients with lung cancer have also failed to demonstrate improved survival. However, AstraZeneca continues to examine the data and intends to pursue additional clinical studies. Other approved treatments for non-small cell lung cancer have been shown to improve survival in clinical trials. Given the results of these studies, it is not reasonable to start new patients on Iressa.

10. What about patients who are already taking Iressa?

Patients who are currently receiving and benefiting from Iressa, or who have taken and benefited from Iressa in the past, may continue to receive the drug. The Iressa Access Program will allow those patients continued access to Iressa. Previously enrolled patients or new patients in non-IND clinical trials approved by an IRB (Institutional Review Board) prior to June 17, 2005 are also eligible to receive Iressa under the Iressa Access Program. Patients enrolled or who may in the future enroll in a clinical trial conducted under an IND may also continue to receive Iressa.

11. Is this decision based on safety concerns?

The main concern is that Iressa would be used in new patients in lieu of other approved treatments that have been shown to improve patient survival. Since the approval of Iressa, Tarceva (erlotinib), an oral drug similar to Iressa, has been approved for treatment of patients with advanced NSCLC who have had prior chemotherapy. Tarceva has been shown in clinical trials to significantly improve patient survival. Taxotere, a chemotherapy drug, has also been shown in clinical trials to improve survival in this group of patients.