Genentech does not explain how it would enroll patients in a new, blinded, controlled trial of Avastin in combination with paclitaxel if this remains a labeled use, CDER says. Furthermore, such a study would likely take many years to complete.
"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 [Supplemental Biologics License Application] requesting an MBC indication."
Chemotherapy Partner Hypothesis Does Not Hold Water
Genentech has hypothesized that chemotherapy partners that provide for prolonged combined exposure with Avastin may result in the strongest treatment effect. Yet this hypothesis has not been substantiated by either clinical or nonclinical evidence, CDER says.
"To support this argument, CDER expects that there should be some proven scientific basis for substantial differences, such as evidence of drug interactions or synergistic/overlapping toxicity between Avastin and other chemotherapy drugs. There is none," CDER says. Evidence submitted to date, such as population pharmacokinetic analyses, suggest no unique interactions between Avastin and any of the chemotherapy agents administered in the trials.
"In the absence of a scientifically supported basis for chemotherapy-specific interactions the more likely explanation for the failure of the clinical trials to verify the results of the E2100 trial is that the magnitude of the PFS treatment effect observed in E2100 is an outlier."
Genentech’s argument on the importance of chemotherapy partner used also runs contrary to its prior position, CDER says, noting that the company initially sought broad approval of Avastin in combination with all taxane-based chemotherapies based solely on the E2100 data.
No One Is Moving Goal Posts at CDER
CDER further disputes Genentech’s argument that it has changed its approval standards for MBC treatments. The regulator consistently maintained in conversations with Genentech that the adequacy of PFS as an approval end point would depend upon the overall dataset and the magnitude of benefit, it says.
"CDER has not in any way sought to ‘move the goal posts,’ " the filing states. "CDER has not determined that a set magnitude of PFS improvement is needed to support an MBC indication; however, CDER has determined that the magnitude of PFS improvement shown in Avastin’s MBC post-approval studies, and shown in the totality of the relevant data, is so small that the risk-benefit balance is unfavorable."
This coverage is provided courtesy of "The Pink Sheet." "The Pink Sheet" and Internal Medicine News Digital Network are both owned by Elsevier.