The basic question for the FDA hearing on the proposal to withdraw Avastin's approval for metastatic breast cancer is whether the Center for Drug Evaluation and Research is using appropriate discretion, according to Genentech's statement on its understanding of the central issues to be resolved.

The accelerated approval regulations "provide that FDA may withdraw an accelerated approval" if the confirmatory trial does not verify the clinical benefit, the April 8 letter from Genentech's counsel allows. "The ultimate question here is whether FDA should withdraw approval of Avastin's MBC indication in light of the facts presented," Covington & Burling attorney Michael Labson continues (emphasis original).

"In particular, the question is whether FDA should withdraw approval when the studies consistently show an efficacy benefit, the benefit is greatest when Avastin is combined with paclitaxel and it is agreed that the safety profile is well-characterized with no new safety signals in the subsequent MBC studies."

The clarification on each party's interpretation of the issues to be resolved is part of the lead up to the June 28-29 hearing on CDER's proposal to withdraw the accelerated approval for metastatic breast cancer for Avastin (bevacizumab) based on the disappointing findings of the confirmatory trials AVADO and RIBBON1 (Also see "Genentech, CDER Tussle Over Avastin Hearing Panel And Format" - Pink Sheet, 28 March, 2011.).

Genentech contends that the FDA commissioner should consider whether the data on Avastin in combination with paclitaxel meets the standard for accelerated approval. The company is proposing to conduct a new confirmatory trial of Avastin with paclitaxel (Also see "Avastin Data, Policy Implications Warrant Hearing On Breast Cancer Use, Genentech Tells FDA" - Pink Sheet, 24 January, 2011.).

The paclitaxel combination in the E2100 trial was the one that proved successful and was the basis of the 2006 accelerated approval of the supplemental metastatic breast cancer claim. The subsequent studies used different chemotherapy agents and did not show meaningful treatment effect, CDER found. The European Medicines Agency opted to maintain the approval for treatment of MBC in combination with paclitaxel while rejecting the attempted expansion for the other regimens.

Genentech has pointed to that decision in its request for a hearing on CDER's proposal to withdraw the MBC indication.

The company also has argued that FDA should look to precedent, both in terms of the safety and efficacy standards and findings for other oncologics and as to whether withdrawal of the Avastin approval "would be consistent with other pertinent FDA approval and withdrawal actions," as the most recent letter reiterates.

The two sides submitted a joint statement on undisputed facts on April 7; Center for Biologics Evaluation and Research's Karen Midthun, the presiding officer for the hearing, requested that the parties specify the areas where they agree and disagree in advance. Both also will submit summaries of their arguments by May 5.

The specific questions Genentech wants addressed at the hearing include whether the benefit-risk profile support availability per "appropriate prescribing information"; whether the differences in PFS between E2100, AVADO and RIBBON1 suggest that the choice of chemotherapy is important to the efficacy of Avastin; and whether the data supporting Avastin plus paclitaxel still meet the standard for accelerated approval "because they establish a reasonable likelihood of clinical benefit with the paclitaxel combination and can be characterized further through an additional study."

More broadly, Genentech also raises the questions of whether withdrawal of the MBC indication "is consistent with FDA's approval of other treatments for first-line metastatic breast cancer" and with precedent from the withdrawal of other products under the accelerated approval program. In keeping with the focus on wider factors, Genentech asks "are FDA's actions on Avastin likely to facilitate or deter the future development of treatments for first-line metastatic breast cancer."

The View Is Much Simpler From CDER's Side

CDER's view, plainly stated, is that Avastin was approved for MBC under accelerated approval authority with the condition that Genentech submit data from post-marketing studies to "'confirm the effect on the clinical endpoint' and 'verify and describe [Avastin's] clinical benefit'" - Genentech submitted that data and CDER concluded that it failed to verify the clinical benefit for the MBC indication and failed to demonstrate that Avastin is safe and effective for that use.

In terms of CDER's first conclusion, the CDER counsel believes the question the Commissioner must consider in evaluating whether CDER's proposal for withdrawal is appropriate is whether the clinical study data verify the clinical benefit of Avastin in MBC, as well as whether the two studies in the second-line setting (the early AVF2119g trial and the post-market RIBBON2) are relevant.

As to whether Avastin is safe and effective for MBC, CDER counsel thinks the Commissioner must specifically consider "whether the minimal effect of Avastin on PFS and absence of a demonstrated effect on length of overall survival, when weighed against the serious adverse reactions attributable to the drug, result in a favorable benefit-risk profile."

The final question, in CDER's view, picks up on part of Genentech's essential argument. That is, whether CDER "has appropriately exercised its authority" by proposing to withdraw the MBC approval rather than keeping the indication on the label while the sponsor designs and conducts additional studies to verify the clinical benefit.

-Mary Jo Laffler (m.laffler@elsevier.com)

Genentech Asks A Lot From Avastin Hearing

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