In a move that could put a serious dent in Genentech's defense of Avastin's metastatic breast cancer indication, FDA's Center for Drug Evaluation and Research is seeking to limit discussion about the company's proposed confirmatory trial for combination use with paclitaxel in first-line MBC at the June 28-29 hearing on withdrawal of the indication.

In a May 17 letter to Karen Midthun, the presiding officer for the hearing, CDER says its discussions with Genentech about potential future trials are irrelevant to proceedings on the proposed withdrawal of bevacizumab's accelerated approval in MBC.

If Midthun agrees with CDER and limits Genentech's ability to discuss future studies, Genentech would be largely stripped of the primary argument it intends to make at the hearing - that accelerated approval should be maintained pending completion of its proposed confirmatory trial with Avastin and paclitaxel in first-line MBC.

CDER's letter also seeks to ban Genentech from presenting evidence regarding the European Medicines Agency's decisions on Avastin in breast cancer. EMA has decided to retain the indication for use with paclitaxel and recently reconsidered its initial rejection of use with capecitabine (Also see "Roche Succeeds In Changing EMA Ruling On Avastin" - Pink Sheet, 15 April, 2011.).

The foreign regulator's views are irrelevant to, and outside the scope of, the U.S. proceedings, CDER maintains.

New Affirmative Evidence Is CDER's Target

The CDER letter was prompted by Genentech's April 25 letter to Midthun, in which the company said it planned to present a limited amount of affirmative evidence beyond the scope of its January submission seeking a hearing on the MBC indication's withdrawal, and then the company's May 13 summary of evidence (Also see "Avastin Hearing's Deadline For Written Submissions Is Indefinitely Delayed" - Pink Sheet, 4 May, 2011.).

The company's affirmative evidence includes reference to a Feb. 22 Type B meeting at which CDER and Genentech discussed the company's proposal for a confirmatory trial of Avastin and paclitaxel in MBC. At that meeting, CDER said that if the study were to demonstrate the magnitude of progression-free survival benefit seen in the E2100 trial, which served as the basis for accelerated approval, such data would support full approval in MBC, according to Genentech.

The Feb. 22 meeting minutes have not been made public as part of the Avastin hearing docket.

The confirmatory trial is the basis of Genentech's argument. In its written summary, the company said it did not intend to base its defense on the AVADO and RIBBON1 studies, which CDER already determined failed to confirm the magnitude of benefit seen with Avastin in the E2100 trial. Rather, the company intended to focus on the question of whether accelerated approval should nevertheless be maintained subject to a further confirmatory trial (Also see "Genentech Appeals To FDA's "Regulatory Flexibility"" - Pink Sheet, 13 May, 2011.).

Genentech initially proposed the new study in August, following the Oncologic Drugs Advisory Committee's overwhelming vote at a July meeting to withdraw the indication. The company's written summary said the trial builds upon the observed difference in the magnitude of effect in E2100, which studied Avastin in combination with paclitaxel, versus the AVADO and RIBBON1 studies, in which other chemotherapeutic agents were studied in combination with Avastin. The proposed study is also premised upon on "the emergence of promising new biomarker data" suggesting greater efficacy in individuals with high plasma VEGF-A concentrations.

Genentech said that since the February Type B meeting it has engaged in further study planning and intends to submit the protocol under a Special Protocol Assessment.

CDER's May 13 summary of evidence said that allowing Avastin to retain the MBC indication while Genentech designs and conducts additional confirmatory trials would jeopardize the integrity of the accelerated approval process (Also see "CDER Says Keeping Avastin Breast Cancer Claim Would Undermine Accelerated Approval Process" - Pink Sheet, 16 May, 2011.).

Withdrawal, Future Studies Travel On Separate "Tracks"

While CDER's written summary of arguments (which was prepared before the agency saw Genentech's document) did not raise an objection to discussion of future trials at the June hearing, the regulator now says details about Genentech's and CDER's discussion on such issues are beyond the hearing's scope.

"CDER does not believe that discussion between Genentech and the center relating to future studies of Avastin are relevant to the center's conclusion that all currently available data - which were submitted to the center over the course of the past several years - have failed to confirm the safety and efficacy of the product in MBC," the May 17 letter states.

CDER will continue to work with Genentech on any plans to pursue additional studies of Avastin in MBC, the regulator said. "However, a plan to conduct a study is simply an expression of a future intention that may or may not be fulfilled. Even if Genentech were to design and conduct one or more additional studies, the results - which may or may not be favorable - likely would not be known for many years."

The letter asserts that the "proper approach" would be to withdraw the MBC indication and allow Genentech to proceed with new clinical trials under the IND framework. "Because CDER views the withdrawal process to be on a separate 'track' from discussions relating to future clinical trials of Avastin, it would not be appropriate for Genentech to present issues discussed at the February 2011 Type B meeting as part of this proceeding."

What Does That Leave Genentech With?

Limiting Genentech's ability to discuss its plans for, and FDA's views of, its proposed confirmatory trial would necessarily heighten the emphasis on the company's remaining key arguments: Avastin's risk/benefit profile remains favorable; other expert bodies and regulatory agencies continue to support Avastin in MBC; and CDER's withdrawal decision is premised upon a new approval standard that may deter development for new treatments in first-line MBC.

But CDER also seeks to take a bite out of the second argument, asserting that evidence of EMA's decision-making is irrelevant and should be excluded from the hearing.

FDA and EMA operate under different regulatory schemes and do not always reach the same conclusions, CDER said. For example, EMA has declined to approve Avastin for treatment of glioblastoma multiforme, an indication that received accelerated approval from CDER, the letter said.

"The focus of this proceeding is whether CDER's proposal to withdraw the MBC indication is appropriate under the U.S. regulatory framework - not whether CDER has reached a different conclusion than the EMA. Accordingly, the decisions of the EMA are not relevant to this proceeding," CDER says.

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

CDER Seeks To Limit Evidence On Future Avastin Studies At June Hearing

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