Company restated proposals in hopes that the agency’s commissioner will reverse ODAC’s decision.
Intent on persuading FDA commissioner Margaret A. Hamburg, M.D., to retain Avastin’s metastatic breast cancer (MBC) indication, Genentech has restated its proposal to conduct a new confirmatory Phase III trial of the drug with the chemo drug paclitaxel in Her2-negative MBC.
In its 133-page post-hearing submission, though, Genentech also proposed that it be allowed to revise labeling for Avastin’s breast cancer indication so that it can be directed toward those patients with aggressive disease and the fewest treatment options, such as people with aggressive hormone receptor positive breast cancer or triple-negative disease.
Additionally, Genentech, a unit of Roche, proposed that it be allowed to implement a Risk Evaluation and Mitigation Strategy (REMS) program and distribute a Medication Guide. The company says that this would support informed treatment decisions by doctors and MBC patients by providing efficacy data for Avastin with paclitaxel for MBC, the differing effects seen with other chemotherapies, and important safety considerations including serious side effects.
Genentech’s proposals, which the company has termed “middle-ground,” come more than a month after an FDA’s Oncology Drug Advisory Committee (ODAC) sided with agency staff officials who concluded that Avastin does not prolong overall survival in patients with breast cancer or offer a benefit in slowing the progression of the disease that outweighs the drug’s risks.
Commissioner Hamburg, however, has final say on whether the FDA will ultimately side with or overrule ODAC. Until then, FDA’s accelerated approval, granted in 2008, remains on the use of Avastin with the chemo drug paclitaxel for women with Her2-negative MBC.
“Withdrawal of access to Avastin for all patients would fundamentally undermine the goals of accelerated approval by prematurely and unnecessarily depriving patients and physicians of a treatment choice where the safety profile is unchanged and well-understood, the confirmatory trials were positive, and a viable study could more definitively confirm clinical benefit,” Genentech stated in its submission, prepared by Sandra J. Horning, M.D., svp, global head, clinical development hematology/oncology; and Michael S. Labson and Paul W. Schmidt, lawyers from Covington & Burling, which represents the company.
A withdrawal of the indication would also shrink Genentech’s $7.7 billion in annual sales generated by Avastin. Avastin was first green-lighted in 2004 for advanced colon cancer and has since been sanctioned for advanced lung, kidney, and brain cancers as well as MBC in combination with paclitaxel. The MBC approval was conditioned on Genentech furnishing additional data on Avastin’s clinical benefit.
Despite an advisory panel’s 5–4 recommendation against the drug, FDA conditionally approved Avastin for MBC, citing Genentech’s E2100 study. It showed a 5.5-month increase in progression free survival (PFS) from 5.8 to 11.3 months.
Last December, however, FDA began efforts to withdraw the MBC indication in line with a Center for Drug Evaluation and Research recommendation after other clinical studies combining Avastin with various chemo drugs failed to replicate or surpass the duration of PFS seen in E2100. Genentech said the later studies still showed some PFS benefit linked to Avastin use, and that the initial 5.5-month PFS was the largest in median PFS observed in a first-line MBC trial.
Genentech and the FDA clashed over what the primary endpoint of clinical studies should be: PFS, as the drug developer is seeking, or overall survival, as the agency wants. At a hearing held over two days in June, ODAC panelists and FDA staffers expressed doubt that a new study would show much better results than earlier studies.
At that hearing and again in its latest submission, Genentech responded by arguing that:
- There are significant unmet medical need in first-line MBC, for which no other medication has been approved since Avastin;
- Avastin in combination with weekly paclitaxel confers a clinically meaningful benefit in first-line MBC. The company cited findings by more than 80 regulatory agencies worldwide that Avastin’s effect varies by chemotherapy partner.
- Avastin’s safety profile supported maintaining the MBC indication. The company noted that were fewer total deaths on Avastin than with chemotherapy alone and no difference in treatment-related deaths.
“Genentech did not previously design a trial to replicate Avastin’s magnitude of effect with paclitaxel because it reasonably understood, from proactively sharing data with CDER as early as 2008 (prior to accelerated approval) showing a lesser magnitude of effect with other chemotherapy partners, that CDER instead sought a consistent showing of improved PFS, which Genentech demonstrated,” the company pointed out in its submission.
“The unforeseen circumstances of this misunderstanding, and the science indicating that the chemotherapy partner affects the magnitude of PFS benefit, provide further support for retaining approval with paclitaxel subject to a confirmatory trial designed to meet the standards CDER has now articulated.”