The novelty and complexity of FDA's upcoming hearing on the withdrawal of Avastin's (bevacizumab) accelerated approval for metastatic breast cancer may be the culprit behind a delay in pre-hearing submissions by Genentech and the Center for Drug Evaluation and Research.

Karen Midthun, FDA's presiding officer for the June 28-29 hearing, has indefinitely postponed the submission deadline for written summaries of the parties' arguments.

The summaries had been due on May 5. However, in a May 2 letter to counsel for Genentech and CDER, Midthun said the submissions will instead be due one week after the formal hearing notice is posted for public review in the Federal Register.

Midthun concedes that the formal notice "will be issued somewhat later than we had intended," but that delaying submission of the parties' written arguments "will give you a better opportunity to address the issues as framed in the notice."

When the notice will be published remains in question. "We do not, at this point, know the exact date on which the notice will be posted," Midthun tells the parties. "A copy will, however, be sent to you on that date."

The delay attached to the publication of the notice in the Federal Register will compress the time available for review of the parties' written submissions by Midthun and the Oncologic Drugs Advisory Committee, which will serve as the panel at the June hearing. The delay also could trickle down to the next milestone in the pre-hearing activities: a May 27 deadline for Genentech and CDER to identify the witnesses they intend to present.

No "New Clinical Trial Data"

Avastin will mark the first time FDA has convened a hearing to withdraw an indication under its accelerated approval regulations. The first-of-its-kind event has presented novel administrative and procedural issues that may have contributed to the agency's delay in releasing the formal notice.

Many of these novel and complex matters are reflected in publicly docketed correspondence between Midthun, Genentech and CDER.

The parties exchanged a series of letters in April regarding the scope of the matters to be considered at the hearing. CDER requested Genentech be precluded from raising or discussing any data or information that was not presented in the company's Jan. 16 submission in response to FDA's notice of opportunity for a hearing.

Genentech disagreed with a unilateral prohibition on discussing new data or information; the company proposed that the parties confer about any new information that is beyond the January submission's scope, with Midthun mediating any disputes.

In response, Midthun said that if Genentech had any new data it wished to present at the hearing, it should disclose this information to CDER by April 25.

In an April 25 letter, Genentech attorneys Michael Labson and Paul Schmidt of Covington & Burling said the company does not intend to present new clinical data the hearing. Rather, it seeks to offer evidence and information outside of its January submission to rebut arguments CDER makes at the hearing.

Rebuttal Evidence

The letter presents several possible areas in which rebuttal evidence might be needed.

Genentech says CDER has indicated that it views the results of two bevacizumab MBC studies - AVF2119g and RIBBON-2 - outside the first-line setting as relevant to determining Avastin's risk/benefit profile in first-line MBC.

Avastin's MBC indication is for first-line use in combination with paclitaxel. The relevance of second-line data is one of several general areas of dispute previously identified by the parties in a joint filing (Also see "Avastin Hearing: Genentech, CDER Dispute Relevance Of Second-Line Breast Cancer Data" - Pink Sheet, 8 April, 2011.).

"Rebuttal information and analyses could include, for example, a description of the protocols of these two studies, which tested Avastin predominantly with non-paclitaxel chemotherapy in patients with more advanced disease; prior statements by CDER officials regarding the relevance of the two studies to Avastin's clinical benefit in first-line MBC; and data demonstrating that Avastin's performance in the RIBBON-2 trial is comparable to the data supporting full approval for other second-line therapies," Genentech says.

Other rebuttal information could include analyses of Avastin's safety in MBC based on data previously submitted to CDER, information from the literature on adverse events, publications supporting the design and conduct of the E2100 study upon which the accelerated approval was granted, and analyses of data submitted to FDA about the effectiveness of Avastin with paclitaxel compared to Avastin with other chemotherapy agents.

The E2100 study assessed Avastin in combination with paclitaxel, but the two confirmatory trials, which failed to show the same magnitude of progression-free survival benefit, were conducted with other chemotherapy agents. Genentech has argued that the choice of chemotherapeutic agent for the combination influences the magnitude of Avastin's effect (Also see "Avastin Data, Policy Implications Warrant Hearing On Breast Cancer Use, Genentech Tells FDA" - Pink Sheet, 24 January, 2011.).

Genentech also expects to offer a "limited amount" of affirmative evidence that is outside the scope of its January submission. This includes European regulators' continued allowance of Avastin for treatment of breast cancer with paclitaxel and with capecitabine, a recent reversal of their earlier decision not to endorse use with that chemotherapy (Also see "Roche Succeeds In Changing EMA Ruling On Avastin" - Pink Sheet, 15 April, 2011.). The affirmative evidence also includes the views of cancer patients, health providers and patient advocates.

The company additionally plans to discuss CDER's statement during a Feb. 22 meeting where the groups discussed Genentech's proposal for a confirmatory trial with a biomarker component to identify the patients who would derive the greatest benefit.

According to Genentech, CDER said that if the study were to demonstrate the magnitude of the PFS benefit seen in the E2100 trial, such data would be sufficient to support full approval in MBC.

-Sue Sutter (s.sutter@elsevier.com)

Avastin Hearing's Deadline For Written Submissions Is Indefinitely Delayed

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