FDA Commissioner Margaret Hamburg faces a decision on the future of Avastin’s (bevacizumab) first-line metastatic breast cancer claim that may not be so cut and dried as the Oncologic Drugs Advisory Committee’s unanimous vote favoring the indication’s withdrawal suggests.

As the final agency arbiter on whether Genentech can retain accelerated approval for Avastin in MBC, Hamburg will have to balance strongly held views from different sides.

On one hand are ODAC and her own Center for Drug Evaluation and Research staff, which strongly favor withdrawal based upon what they see as the lack of evidence of clinical benefit.

On the other side are Genentech, which seeks to preserve millions in sales for one of its biggest-selling products; impassioned breast cancer patients and providers upset about the potential loss of insurance coverage; and lawmakers who have already criticized CDER’s proposal to revoke the indication as a sign of health care “rationing” by the Obama administration.

These factors combine to create a politically difficult decision for Hamburg, who has led FDA for two years. Yet, there could be an alternative to a black-or-white, withdrawal-or-not action on Avastin, one that limits the biologic’s use to current MBC patients who have demonstrated benefit.

Ultimately, any decision Hamburg makes on Avastin will affect how the accelerated pathway is viewed and used by both sponsors and CDER in the years to come.

Three Trials, Unconvincing Efficacy

In their votes at the conclusion of the June 28-29 hearing, ODAC members uniformly said that the 5.5-month median progression-free survival advantage seen in the E2100 trial, which served as the basis for accelerated approval, was not verified by the AVADO and RIBBON1 studies.

The median PFS benefit seen in these later studies ranged from less than one month to three months, and this was not clinically significant given the absence of any improvement in overall survival or health-related quality of life, panel members said.

The committee unanimously opposed retaining the MBC indication while Genentech conducts another confirmatory trial of bevacizumab in combination with paclitaxel, the use for which it is currently approved (Also see "New Avastin Breast Cancer Study Proposal Not Enough To Save Current Claim, ODAC Concludes" - Pink Sheet, 29 June, 2011.).

ODAC Member	Affiliation
Frank Balis	Children’s Hospital of Philadelphia
Gregory Curt¹	AstraZeneca Oncology
Ralph Freedman	University of Texas M.D. Anderson Cancer Center
Brent Logan	Medical College of Wisconsin
Natalie Compagni Portis²	Breast cancer patient
Mikkael Sekeres	Cleveland Clinic Taussig Cancer Institute
Wyndham Wilson³	National Cancer Institute
1 Non-voting industry representative 2 Temporary voting member/patient representative 3 ODAC Chairman

Issue	ODAC Vote
Do AVADO, RIBBON1 trials fail to verify Avastin’s clinical benefit in the approved MBC indication?	Y - 6, N - 0
Does the evidence demonstrate that Avastin has not been shown effective for the approved MBC indication?	Y - 6, N – 0
Does the evidence demonstrate that Avastin has not been shown safe for the approved MBC indication?	Y - 6, N – 0
Should Avastin’s MBC claim remain pending additional confirmatory studies?	Y - 0, N - 6

The new trial was the cornerstone of Genentech’s defense. The company said it should have an opportunity, with the MBC indication still on-label, to validate its theory that Avastin’s efficacy depends upon the specified chemotherapy partner used and the duration of chemotherapy. The company also seeks to validate high VEGF-A levels as a predictive biomarker of efficacy (Also see "Genentech Appeals To FDA's "Regulatory Flexibility"" - Pink Sheet, 13 May, 2011.).

The company has proposed a new randomized study of 480 patients, with an interim analysis for “regulatory futility” after 220 PFS events, approximately 3.5 years after the study begins. Enrollment is targeted to begin in the first quarter of 2012, and the final study report would not be expected until late 2016 at the earliest.

CDER officials said Genentech’s proposed trial is unlikely to substantiate the magnitude of PFS benefit seen in E2100, and they challenged the company’s ability to enroll U.S. patients if the indication remains on-label (Also see "CDER Attacks Genentech's Plans For New Confirmatory Trial At Avastin Hearing" - Pink Sheet, 28 June, 2011.).

The Next Steps

FDA hearing official Karen Midthun said that after the public docket closes on July 28 she will work with Hamburg to draft a written document that explains the basis for the ultimate decision.

Hamburg has several clear options at her disposal.

She could opt for full rescission of the claim, a move certain to draw lawsuits as well as outrage from some Republicans on Capitol Hill, setting the stage for congressional hearings.

An FDA withdrawal decision on the MBC claim would not affect Avastin’s continued market availability, as the VEGF-inhibitor’s indications for lung, colon and brain cancers would be unaffected. Nevertheless, taking the MBC claim off the label could result in decisions by insurers to deny coverage for this use.

While issues related to drug costs and reimbursement are technically outside FDA’s purview, they always hover in the background. Potential loss of reimbursement coverage was a key reason cited by some of the dozens of breast cancer patients who testified against withdrawal during the open public session of the Avastin hearing.

The Centers for Medicare and Medicaid Services said on June 30 that an FDA withdrawal decision would not lead Medicare to drop coverage for Avastin in MBC. “It is not uncommon for us to pay for off-label uses of Part B drugs,” the CMS spokesman said.

Alternatively, Hamburg could decide the evidence does not support altering or withdrawing the indication while Genentech conducts another study. This option seems unlikely, however, given the strong views of CDER staff and ODAC in support of withdrawal, and it would appear to go against her own emphasis on a science-based approach to drug regulation.

Hamburg has spoken publicly of the need for FDA’s decisions to be grounded in science.

During the July 2010 advisory committee meeting on another troubled drug, GlaxoSmithKline’s diabetes treatment Avandia, she urged the panelists to "follow the science, wherever it leads, and the rest will fall into place" (Also see "Avandia Advisory Committee Re-Review Reflects Well On FDA" - Pink Sheet, 19 July, 2010.).

A decision to allow continued marketing of Avastin in MBC would be widely viewed as a repudiation of this science-centric focus.

Such an action by Hamburg, a political appointee, would be demoralizing to the Office of Oncology Drug Products and could undermine the ability and willingness of CDER career staff to consider drugs for accelerated approval.

The argument could be made that if FDA allows the MBC indication to stand in any form, CDER officials will become less inclined to grant accelerated approval because they will lack confidence in the recourse of withdrawal.

Following In Iressa Or Avandia’s Footsteps?

A third, though less well-defined, option appears to exist: allowing Avastin to remain on label, but for a more restricted MBC population than is currently indicated. This approach would serve to dissuade widespread use but could allow Avastin to remain available and reimbursable for women who are currently taking the biologic and benefitting as a result.

Such an approach could be modeled upon restrictions already in place with two other drugs.

FDA could follow the narrowed indication adopted for AstraZeneca’s non-small cell lung cancer treatment Iressa (gefitinib) in 2005. Iressa initially received accelerated approval, but a subsequent confirmatory trial failed to demonstrate a survival benefit.

Rather than withdrawing the drug, the agency limited use to those patients who had already received gefitinib and benefitted from it. FDA also instructed AstraZeneca to design a restricted distribution plan (Also see "Iressa Gets Narrowed Indication Instead Of Withdrawal: New Model For FDA?" - Pink Sheet, 27 June, 2005.).

While Iressa still remains available in the U.S. under such restrictions, AstraZeneca recently announced it will withdraw the drug in September 2011.

FDA’s handling of Avandia also reflects flexibility in working to keep a troubled drug on the market.

In deciding against withdrawal of rosiglitazone, FDA required the indication be narrowed to only those patients already taking Avandia or those for whom it would amount to a last resort. It also required restricted distribution under a Risk Evaluation and Mitigation Strategy (Also see "Avandia REMS Requires Doctors To Tell Patients About Actos’ CV Safety" - Pink Sheet, 23 May, 2011.).

Suggested Labeling Restrictions

Genentech said it is willing to discuss modifying or restricting the current MBC indication while a new confirmatory study is conducted. The company also previously said it would develop a REMS with a communication plan and a medication guide. However, there was no discussion of the REMS at the hearing, and Midthun requested details about the proposal be submitted to the docket.

Joyce O'Shaughnessy, a breast cancer specialist at Baylor University Medical Center and a Genentech consultant, urged CDER to retain Avastin's MBC indication for patients with triple-negative or aggressive, estrogen receptor-positive disease while the confirmatory study is underway.

However, Division of Biologic Oncology Products Director Patricia Keegan presented data from the E2100, AVADO and RIBBON1 studies showing no major treatment differences among those with triple-negative disease and those who are HER-2 negative but ER-positive, suggesting that carving out such a population would not be supported.

By Sue Sutter

Avastin’s Breast Cancer Claim: Will FDA’s Hamburg Take A Middle Road?

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