Genentech and FDA’s Center for Drug Evaluation and Research seem to agree on one thing when it comes to deciding whether Avastin’s (bevacizumab) metastatic breast cancer indication should be withdrawn – the integrity and intent of the agency’s accelerated approval program are at stake.

However, the parties clearly diverge on the reasons why and how the accelerated approval mechanism would be damaged depending upon the action taken.

In separate May 13 summaries of evidence they intend to present at a June 28-29 hearing on the indication’s fate, both Genentech and CDER say that doing as the other party wishes would undermine the accelerated approval process and contravene the interests of public health.

The filings reflect the enduring impact that the Avastin imbroglio – which marks the first time a sponsor has challenged CDER’s bid to withdraw an indication under the accelerated approval process – is likely to have on the program.

Evidence Summaries Delayed

The documents summarize the arguments Genentech and CDER will make to FDA presiding officer Karen Midthun and the Oncologic Drugs Advisory Committee at the June hearing on CDER’s proposal to withdraw approval of Avastin’s claim for first-line MBC in combination with paclitaxel.

The submissions were delayed more than a week so that the parties could frame their arguments around the three issues that Commissioner Margaret Hamburg expects to decide upon and which will be the focus of the hearing: whether the AVADO and RIBBON1 trials failed to verify Avastin's clinical benefit in MBC as seen in the pivotal E2100 study, whether the available evidence shows Avastin is safe and effective for MBC, and whether FDA should withdraw the MBC approval.

Even if Hamburg were to determine that the grounds for withdrawing the MBC claim have been met, she nevertheless could decide to retain the indication while Genentech conducts additional studies to confirm clinical benefit (Also see "An Avastin Loophole: Hamburg Could Decide To Retain Approval During Confirmatory Trial" - Pink Sheet, 9 May, 2011.).

Genentech is centering its argument on the proposal for a new confirmatory trial (Also see "Genentech Appeals To FDA's "Regulatory Flexibility"" - Pink Sheet, 13 May, 2011.).

The company said it was not going to contest the agency's interpretation of the AVADO and RIBBON1 trials, which studied Avastin in combination with non-paclitaxel chemotherapies. CDER has determined the studies failed to confirm the magnitude of benefit seen with Avastin in the E2100 trial, which studied bevacizumab with paclitaxel and served as the basis for accelerated approval.

"The only open question is whether the magnitude of benefit observed in the E2100 study is reasonably likely to be confirmed in a second study of Avastin with paclitaxel," the company argued.

Genentech first proposed conducting a new confirmatory trial in August 2010, one month after ODAC voted against continued approval in MBC.

The double-blind, randomized, multicenter Phase III trial of Avastin plus weekly paclitaxel would include a biomarker component to select for patients more likely to derive a greater benefit from treatment. "Based on the company's extensive research, including a new assay sensitive to specific isoforms, plasma concentration of VEGF-A (Avastin's target) has been identified as a potential predictive biomarker in breast, gastric and pancreatic cancers," its summary states.

The company met with CDER on Feb. 22 to discuss the study proposal. At that meeting, according to Genentech, CDER said that if the study were to demonstrate the magnitude of progression-free survival benefit seen in the E2100 trial, such data would support full approval in MBC.

CDER has moved to bar Genentech from introducing evidence of the Feb. 22 meeting at the hearing, asserting that its discussions with the company about potential future trials are irrelevant to proceedings on the proposed withdrawal of the MBC indication (Also see "CDER Seeks To Limit Evidence On Future Avastin Studies At June Hearing" - Pink Sheet, 18 May, 2011.).

The regulator has taken the position that the additional trial, if run, should be submitted as an sBLA, but that the MBC indication should not remain on-label while the study is conducted.

Public Health Implications Of Withdrawal

Genentech says the public health would not be served by revoking the MBC indication. Withdrawing accelerated approval is only appropriate when “there is no reasonable likelihood of clinical benefit and no possibility that additional study might further characterize any existing benefit,” the company argues.

Withdrawal would be adverse to public health because post-marketing studies uncovered no new safety risk and continued to show a PFS benefit, Genentech said.

It would be contrary to public health to withdraw accelerated approval, the company said, because the AVADO and RIBBON1 studies uncovered no new safety risks and continued to show a PFS benefit, albeit at a lower magnitude with different chemotherapy partners.

“Withdrawal here would fundamentally undermine the goals of the accelerated approval program by prematurely and unnecessarily depriving a vulnerable patient population of a valuable therapy,” it concludes in the summary of evidence.

These public health concerns are compounded by the limited treatment options for first-line MBC, “against which Avastin compares favorably,” the summary states. The filing points specifically to data on Lilly’s Gemzar (gemcitabine) suggesting a time-to-progression benefit of 2.3 months, compared with the 5.5-month median PFS advantage seen in the E2100 study. (Median improvement in PFS was 0.9 months in AVADO and 1.2-2.9 months in RIBBON1.)

By drawing comparisons between Avastin and other MBC treatments, the company may be attempting to walk down a road that is already blocked off. The agency’s formal notice for the June hearing specifically rejected Genentech's bid to introduce evidence of other MBC product approvals and other accelerated approval drugs.

In the evidence summary, Genentech said it understood it was precluded from challenging the consistency of CDER’s regulatory decisions but not prohibited from discussing how Avastin’s safety and efficacy data compare to that of other MBC treatments.

Genentech also invokes the public health impact in its assertion that CDER’s proposed withdrawal rests on a new, and not clearly defined, approval standard that may deter development of new drugs.

“The proposal for Avastin’s withdrawal suggests that either a substantial PFS improvement (replicating or exceeding the results of the E2100 study) or an [overall survival] benefit is necessary for approval,” the company says. “The agency has not clearly and consistently articulated, or applied, this new standard, creating an unpredictable regulatory setting and risking confusion among oncologic drug sponsors that may deter future development in MBC. This lack of predictability and consistency raises special concerns in an area of high unmet medical need.”

Ultimately, Genentech makes an appeal for the agency to exercise its “regulatory flexibility” under the accelerated approval regime. “Regulatory flexibility is intended for cases like this," the summary concludes, "where a formulaic application of the withdrawal standard would deprive patients and physicians of the choice intended by the accelerated approval program – and do so in the face of continued findings of benefit, a well-understood safety profile, and a viable option for providing a clearer answer to the remaining scientific questions."

Withdrawal Is Accelerated, Too

CDER takes a different view of its obligations under the accelerated approval process and of how the program was meant to operate, focusing on the element of “accelerated withdrawal.”

The regulator’s ability to withdraw approval expeditiously when confirmatory trials fail to verify clinical benefit is a central tenet of the program, according to CDER’s evidence summary. Allowing Genentech to maintain the MBC claim while it conducts an additional study would render the accelerated approval process a lower approval standard and is inconsistent with the interests of public health.

The accelerated approval rubric does not contemplate maintaining an indication pending more confirmatory studies, CDER said.

“Once post-approval trials fail to demonstrate the expected clinical benefit, the accelerated approval rubric does not contemplate – as Genentech argues –that the agency should ‘maintain’ approval while an applicant designs and conducts more trials with the hope of eventually verifying clinical benefit,” the regulator says.

“If CDER were forced to allow products to stay on the market when the risk-benefit analysis shows that the product is not safe and effective for its intended use, the accelerated approval program would be significantly undermined.”

The agency takes issue with Genentech's assertion that the indication should be maintained as long as the data for Avastin in combination with paclitaxel continue to be reasonably likely to predict clinical benefit.

The "reasonably likely" language in the accelerated approval regulations refers to the relationship between a surrogate endpoint and clinical benefit, CDER explains. "In the case of Avastin's MBC approval, there was no surrogate endpoint – CDER believed that 5.5 months of PFS could be deemed a clinical benefit, subject to confirmatory trials."

"Rather than serving as a basis to 'maintain' approval, which is not part of the accelerated approval program, the new research proposed by Genentech, if completed favorably, could be used to support a new sBLA requesting an MBC indication."

CDER further asserts that Genentech’s hypothesis justifying a new Avastin/paclitaxel trial – that chemotherapy partners enabling prolonged combined exposure with Avastin may yield the largest treatment effect – has not been substantiated by clinical or non-clinical evidence. The regulator also disputes Genentech’s assertion that it has changed its approval standards for MBC (Also see "CDER Says Keeping Avastin Breast Cancer Claim Would Undermine Accelerated Approval Process" - Pink Sheet, 16 May, 2011.).

The parties also used their evidence summaries to snipe at each other over the qualifications of ODAC members and the relevance of other regulators’ and expert bodies’ views on Avastin in MBC (see related story, Also see "Genentech, CDER Spar Over Third-Party Views On Avastin Breast Cancer Claim" - Pink Sheet, 23 May, 2011.).

By Sue Sutter

Accelerated Approval Program’s Future Is On The Line At Avastin Hearing

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