FDA is leaving an opening for Genentech to hold on to Avastin's metastatic breast cancer indication even if Commissioner Margaret Hamburg determines existing evidence has not demonstrated bevacizumab's efficacy or safety for this use.

Hamburg can decide to retain bevacizumab's accelerated approval in first-line MBC while the company conducts additional studies to confirm clinical benefit even after determining that the grounds for withdrawing the claim have been met, the agency says in a Federal Register notice announcing the June 28-29 hearing on the Center for Drug Evaluation and Research's proposal to withdraw the indication.

The notice identifies three issues related to the statutory and regulatory standards for FDA withdrawal of the MBC indication that Hamburg expects to decide upon and which will be the focus of the hearing.

The first is whether the AVADO and RIBBON-1 trials failed to verify Avastin's clinical benefit for first-line MBC.

The two studies were intended to serve as confirmatory trials for Avastin's accelerated approval in first-line MBC in combination with paclitaxel. AVADO studied the addition of Avastin to docetaxel, while RIBBON-1 examined Avastin in combination with taxane/anthracyclinc-based chemotherapy or capecitabine. Although both showed a significant improvement in progression-free survival, CDER concluded they failed to verify the magnitude of PFS benefit seen in the E2100 trial, upon which accelerated approval was granted.

The second issue, subdivided into two parts, is whether the available evidence on Avastin demonstrates that the drug has not been shown a) effective or b) safe for the MBC indication.

This question will hinge on the evidence of effectiveness in MBC and the appropriate risk/benefit analysis given the drug's known safety issues. "FDA does not anticipate that the hearing will involve any dispute about the safety information in the clinical studies," the notice states.

If the commissioner agrees with the grounds for withdrawal encompassed in the first two issues, the third and final issue to be decided is whether FDA should nevertheless retain approval of the breast cancer indication while Genentech designs and conducts additional studies to verify clinical benefit in MBC.

"If Genentech prevails on issues 1, 2. a) and 2. b), the approval will be continued," the notice states. "If CDER prevails on issue 1, 2. a) or 2. b), the question of withdrawal will depend on issue 3."

A decision on the third issue is necessary because both the FD&C Act and FDA's accelerated approval regulations "do not by their terms require the withdrawal of an accelerated approval even if the bases for withdrawal they describe are present," the notice states.

"Instead, in each case, the statute and regulation state that FDA 'may' withdraw approval in those circumstances. This standard reflects the fact that decisions on withdrawals of approval of products necessarily reflect judgment on FDA's part as to what actions are appropriate to protect the public with respect to approved products, and what uses of those products should be stated on the labels of those products."

Scrutinizing Genentech's Confirmatory Trial Proposal

Should she reach the third issue, Hamburg's deliberations will be influenced by Genentech's existing proposal for a confirmatory trial of Avastin in combination with paclitaxel and whether the study is reasonably likely to demonstrate a clinical benefit in first-line MBC.

Genentech asserts that Avastin's magnitude of benefit varies depending upon the chemotherapy agent with which the VEGF inhibitor is paired. In its January request for a hearing, the company said it should have the opportunity to conduct another study, while accelerated approval is maintained, to establish paclitaxel as the preferred chemotherapy partner (Also see "Avastin Data, Policy Implications Warrant Hearing On Breast Cancer Use, Genentech Tells FDA" - Pink Sheet, 24 January, 2011.).

The company had already submitted a proposal to FDA for a confirmatory, double-blind, randomized, multi-center Phase III study of Avastin with paclitaxel, a month after the July 2010 Oncologic Drugs Advisory Committee's overwhelming vote to remove the MBC indication.

The primary efficacy endpoint of the new confirmatory trial would be PFS, with overall survival, one-year survival and response rate as secondary endpoints. The study also would include a biomarker component to identify patients who may be more likely to benefit from Avastin.

There was no specific mention of this proposed trial, however, in CDER's Dec. 15, 2010 decision memo recommending withdrawal of the breast cancer indication.

In that memo, Office of Oncology Drug Products Director Richard Pazdur wrote: "Genentech is encouraged to further develop Avastin in breast cancer to identify patient subsets who are likely to benefit in a risk/benefit evaluation. No current subgroup analyses have demonstrated this evidence. We strongly urge Genentech to submit future trials under special protocol assessments to ensure agreement with the agency."

Pazdur was definitive in his view of the existing evidence, saying, "No trial in breast cancer using Avastin provides evidence of direct clinical benefit. Modest effects on primarily radiographic outcomes were demonstrated."

Nevertheless, Genentech's proposed confirmatory study has been the focus of subsequent discussions between the company and CDER.

According to a recent letter submitted by Genentech to the Avastin hearing docket, the parties held a Feb. 22 meeting at which CDER said that replication of the magnitude of PFS benefit seen in the E2100 study in Genentech's proposed confirmatory trial would be sufficient to support full approval for first-line MBC

Evidence Of Other Product Approvals Excluded

While the hearing notice delineates the focal issues for the commissioner and, consequently, the hearing, it specifically rejects Genentech's bid to bring other MBC product approvals and other accelerated approval drugs into the mix.

The company argued that by seeking to revoke Avastin's MBC indication, CDER is creating a new approval standard that will negatively affect cancer drug development, and that other therapies already cleared for this use have not had to meet the evidentiary hurdles that FDA is requiring of bevacizumab. Withdrawal of Avastin's MBC claim also would depart significantly from other accelerated approval withdrawals, the company maintained (Also see "Avastin Hearing: Genentech, CDER Dispute Relevance Of Second-Line Breast Cancer Data" - Pink Sheet, 8 April, 2011.).

However, the notice makes clear that other product approvals are irrelevant to the matters at hand.

"Each decision to withdraw or not to withdraw the approval of a product must be made on its own merits," the notice states. "If the decision with respect to another product is in error, that would not justify continuing that error with respect to the MBC indication for Avastin. Moreover, as a practical matter, it would not be possible to evaluate the different circumstances associated with decisions with respect to other products in the context of this or any hearing."

FDA Reverses Course On Public Testimony

Although the agency's decision to exclude evidence of other product approvals comes as a big blow to Genentech, the company should find some solace in FDA's decision to allow two hours of open public testimony during the hearing's first day.

The decision to allow oral presentations by individuals other than the parties is a reversal; as recently as March 29, Karen Midthun, the hearing's presiding officer, had rejected Genentech's request to allow members of the public to speak at the hearing (Also see "Genentech's Hopes For Avastin In Breast Cancer May Rest With New ODAC Members" - Pink Sheet, 4 April, 2011.).

The hearing notice provides no explanation for the reversal. In an emailed response to questions from "The Pink Sheet" DAILY, FDA said Midthun sent a May 6 letter to ODAC - which will serve as the panel for the hearing - indicating she decided to include a public session "in response to an expressed interest in having an opportunity for the public to speak."

The change will enable Genentech to mobilize supporters within the patient and provider community to speak at the hearing.

The delay in issuing the formal notice, which was posted for public inspection at the Federal Register website on May 9, prompted Midthun to postpone the submission deadline for written summaries of Genentech's and CDER's arguments (Also see "Avastin Hearing's Deadline For Written Submissions Is Indefinitely Delayed" - Pink Sheet, 4 May, 2011.).

The new deadline for written summaries is May 13. The notice states that the hearing will be held at the agency's White Oak campus from 8 a.m. to 5 p.m. both June 28 and 29.

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

An Avastin Loophole: Hamburg Could Decide To Retain Approval During Confirmatory Trial

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