Genentech's Avastin may not have produced a storybook ending in metastatic breast cancer, but it still serves as an example of how the accelerated approval process can work.

As Oncologic Drugs Advisory Committee members were preparing to vote 12-1 in favor of removing the breast cancer indication for the drug, Richard Pazdur, director of FDA's Office of Oncology Drug Products, still had to tell them the vote would not confirm the agency made a mistake.

"Let me absolve you of your guilt," Pazdur said to another committee member, who was concerned. "We do not look at this as a mistake. We look at this as part of the process basically of accelerated approval. And drugs will come off accelerated approval because there is a risk here in approving these drugs and this is management of that risk."

But even as Pazdur assured the committee that reversing an accelerated approval was a natural part of the regulatory process, he noted that FDA was taking steps to better clarify how sponsors should handle their commitments under the approval mechanism.

Based on the results of its E2100 trial, which showed massive improvements in progression-free survival when combined with paclitaxel, Avastin (bevacizumab) gained an accelerated approval in 2008. Median PFS in the Avastin arm was 11.3 months compared to paclitaxel alone, which was 5.8 months.

Committee members unanimously decided July 20 the results of two confirmatory trials did not support moving the drug to full approval for metastatic breast cancer treatment when combined with paclitaxel, although there was some debate about what the statistical threshold for clinical benefit should be (see ¹ Also see "Avastin Breast Cancer Approval Debate Pits Clinical Benefit Versus Statistics" - Pink Sheet, 26 July, 2010.).

Several committee members who were relatively encouraged by the data in 2007 when ODAC reviewed the E2100 results now emphasized that the drug had failed. While the vote at that time was 5-4 against approval, several said they were excited about Avastin's potential.

"My thought process [in 2007] was as somebody who takes care of these patients, and more than a doubling of response rate and a doubling of the progression-free survival is incredibly meaningful," said Joanne Mortimer, director, women's cancers program, City of Hope Comprehensive Cancer Center. "With data from trials that are robust and it's sponsored by the pharmaceutical company making the drug, it's really hard to justify keeping this as a label indication for Avastin."

Pazdur's soothing of committee members' bad feelings may have been because some did not entirely realize the additional trials, no matter the outcome, were part of the accelerated approval process, said ODAC Chairman Wyndham Wilson, chief, Lymphoma Therapeutics Section, National Cancer Institute.

"This is a good example of the system working," Wilson said.

Jean Grem, professor of medicine at the University of Nebraska, who initially said that voting against the drug now would be essentially saying that FDA's initial decision to approve Avastin for the indication was a mistake, said later she was no longer ashamed of the decision.

"Obviously we're all disappointed with the results of these follow-up studies, but since Dr. Pazdur has absolved me of guilt I will hold my head up high," she said.

How Many Trials Are Enough?

Part of the accelerated approval process for Avastin was to require the two additional studies to confirm the PFS results.

Pazdur all but said definitively that Avastin's accelerated approval is in jeopardy based on the data from the AVADO and RIBBON-1 trials. When asked whether the company could do more trials to try and confirm the E2100 results, Pazdur said FDA regulations allow for it, but the agency can stop them.

"In some situations one cannot do the confirmatory trial in the same population and we realize that," he said. "But in this situation we now have ... [there's a] comprehensive database of three trials with thousands of patients treated and what you see is what you get basically as far as the clinical benefit for a first-line breast cancer indication with chemotherapy."

Genentech issued a statement after the hearing stating it stands by its data and that Avastin should remain an option for metastatic breast cancer patients.

The company also has two more Phase III trials involving Avastin in metastatic breast cancer that it plans to submit (² Also see "Avastin's Last Hope For Breast Cancer Claim May Be Subpopulations" - Pink Sheet, 20 July, 2010.).

ODAC Will Talk About "Due Diligence"

Committee members questioned whether Avastin would ever have its accelerated approval withdrawn, unless Genentech chooses to do it voluntarily.

"In groups that I deal with, they say once you get accelerated approval you can sit back and rest because it takes forever to move it off one way or the other," said Ralph D'Agostino, chair of the mathematics and statistics department at Boston University. "I think that this is a point where we have a vote to actually put together the data we have and what does that say about fulfilling the added requirements."

An example of the long accelerated approval period was Pfizer's leukemia therapy Mylotarg (gemtuzumab). As the first accelerated approval NDA withdrawn, it was not pulled for 10 years (³ Also see "Pfizer Pulls Mylotarg For Safety 10 Years After Accelerated Approval" - Pink Sheet, 28 June, 2010.).

Pazdur said sponsors are supposed to complete confirmatory trials with due diligence, but there is no regulatory definition of that time period. He defined it as moving at a pace similar to any drug registration.

Now Pazdur may be considering shifting his handling of commitments under the accelerated approval process. He said there will be an ODAC meeting next year to talk about it.

"Our problem is not so much the negative trials or perception of a negative trial, but sponsors really completing their trials with what many people might consider due diligence," Pazdur said.

- Derrick Gingery ( ⁴ d.gingery@elsevier.com )

Accelerated Approval: Mend, Don't End, Pazdur Tells ODAC After Avastin

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