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AstraZeneca Withdraws Iressa Accelerated Approval NDA; Rules out Refiling with PGx Data


By Turna Ray

AstraZeneca announced earlier this month that it will not seek approval from the US Food and Drug Administration for its EGFR tyrosine kinase inhibitor Iressa as a treatment for non-small cell lung cancer.

"AstraZeneca does not plan to pursue approval for Iressa in the US," the company said in a statement. Furthermore, AstraZeneca has informed the FDA that it will be withdrawing its accelerated approval new drug application for Iressa as of Sept. 30.

A spokesperson from AstraZeneca told PGx Reporter that although the decision to withdraw its accelerated approval NDA doesn't preclude the company from filing an entirely new NDA for Iressa in NSCLC patients with EGFR mutations, as it has done in several European countries, AstraZeneca has decided not to try to relaunch Iressa with a PGx strategy in the US.

The firm informed US patients taking Iressa, along with their doctors, that "patients currently benefitting from Iressa therapy will be able to continue to receive treatment through a clinical study." However, the trial is not meant to gather data for a new NDA, said Blair Hains, AstraZeneca's director of brand corporate affairs. Rather, the study aims to maintain access to Iressa for the few hundred lung cancer patients in the US who choose to remain on the drug.

In the next six months, AstraZeneca will contact patients currently receiving Iressa and their physicians to facilitate enrollment in the trial. The company is hoping to fully withdraw its accelerated approval NDA for Iressa before the Sept. 30 deadline.

The FDA green-lighted Iressa under its accelerated approval program in 2003 as a treatment for patients with locally advanced or metastatic NSCLC. However, in 2005, after a large randomized trial failed to demonstrate a survival advantage for those taking Iressa, the agency decided to keep the drug on the market under a limited-access scheme. Under this program, patients already taking Iressa and benefitting from it could continue to get the drug.

Around the same time Iressa's availability was restricted in the US, AstraZeneca withdrew its application for the drug in the European Union. However, in the European market, the company was able to reapply for marketing approval in 2008, showing the drug was effective in EGFR-positive patients. In 2009, European regulators approved Iressa as a treatment for locally advanced or metastatic NSCLC patients whose tumors have EGFR mutations.

Additionally, last year, the UK's National Institute for Health and Clinical Excellence recommended that the National Health Service should pay for Iressa in the first-line treatment setting if patients test positive for EGFR mutations and if the drug developer provides the drug at a fixed price (PGx Reporter 06/02/10).

Through FDA's accelerated approval program, drug sponsors can receive expedited marketing approval for drugs to treat life-threatening illnesses for which there are limited options. Accelerated approval is granted when health regulators have determined that it may take sponsors several years to obtain data showing the drug improves outcomes in patients compared to available treatments.

The FDA grants drugs accelerated approval based on their impact on surrogate endpoints. Iressa's accelerated approval was based on a surrogate endpoint looking at how patients' tumors responded to the drug. Early studies showed that the tumor response rate in patients taking the drug was approximately 10 percent.

After receiving accelerated approval, however, a sponsor is required to conduct post-marketing trials that move beyond surrogate endpoints and prove that the drug truly impacts clinical outcomes for patients. Under the Food and Drug Administration Amendments Act of 2007, sponsors can face monetary penalties for failing to complete post-marketing studies with "due diligence."

The fact that AstraZeneca withdrew its accelerated approval NDA for Iressa may signal that it was having trouble recruiting patients for studies in the US. The drug's efficacy shortcomings in the general population were highly publicized and the treatment was available through a limited access program for those already benefitting.

Furthermore, in studies previously submitted to the FDA, AstraZenca was unable to show that Iressa-treated patients had a survival advantage over patients receiving standard chemotherapy regimens.

UK's NICE decided to pay for genetic testing based on results from the Iressa in the pivotal Iressa Pan Asian Study, or IPASS, which showed that EGFR mutation-positive patients treated with Iressa experienced longer progression-free survival compared to patients treated with the carboplatin/paclitaxel chemotherapy combination. However, when it came to overall survival, there was no statistically significant difference between the two arms. Perhaps Iressa's lack of impact on overall survival was a problem for the FDA.

Hains maintained that conversations between the FDA and AstraZeneca were confidential. He added, however, that after speaking with the agency AstraZeneca felt that it would not be able to convert the accelerated approval NDA for Iressa into full approval.

AstraZeneca's decision to withdraw its accelerated NDA for Iressa was discussed this week at a meeting of the FDA's Oncology Drugs Advisory Committee meeting, where five companies discussed their challenges meeting post-marketing requirements for drugs that received accelerated approval. Richard Pazdur, director of the agency's Office of Oncology Drug Products, noted that several companies did not want to present at the meeting, and instead decided to withdraw their accelerated approval NDA altogether.

The ODAC meeting was held to discuss potential improvements to the accelerated approval process for oncology drugs. Pazdur noted that the agency and sponsors needed to work together to map out a plan for meeting accelerated approval post-marketing commitments in a timely fashion and perhaps start randomized-controlled trials earlier.

According to, AstraZeneca is currently recruiting patients for several clinical trials for the use of Iressa in NSCLC, but most of these trials are being conducted outside the US, in Asian or European populations. Several of these studies are considering EGFR mutation status as a recruitment criterion.

Hains noted that the US Iressa access trial is still in the planning stages and has not been listed on Patients who were previously paying for Iressa will receive the drug for free through the clinical study.

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