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Genentech Gets Public Hearing on Avastin, but Remains Coy on Discussing PGx Data

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Originally published Feb. 25.

By Turna Ray

The US Food and Drug Administration has granted Genentech a public hearing where the company will get a last shot at trying to convince the agency to reverse its decision to revoke Avastin's approval as a treatment for breast cancer.

In a document appealing FDA's decision to revoke Avastin's approval as a breast cancer drug, Roche subsidiary Genentech raised the possibility of conducting biomarker analysis to guide treatment to best responders. However, a company spokesperson this week could not verify that the company will definitely discuss pharmacogenomics data at the June 28-29 hearing.

Following the recommendation of FDA's Oncology Drugs Advisory Committee, the agency last year announced it would revoke Avastin's accelerated approval in the metastatic breast cancer setting. This decision was informed by data from post-marketing studies that showed the drug did not significantly impact patients' overall survival and caused serious adverse reactions (PGx Reporter 12/22/10).

At the public hearing slated for June 28-29, ODAC will once again be hearing from Genentech and FDA experts about whether Avastin should remain a treatment option for breast cancer patients. FDA Commissioner Margaret Hamburg will be presiding over the meeting.

The FDA instructed Genentech and FDA's Center for Drug Evaluation and Research to "consult together" ahead of the hearing and "prepare a joint statement of those facts that are not in dispute and of those that are disputed." Once this joint statement is submitted, Genentech and CDER will have to separately enumerate the arguments and evidence they wish to present at the meeting.

On the first day of the two-day hearing, committee members will hear presentations from CDER and Genentech. Members of the public can submit statements in writing, and these will be available through the public docket. However, oral public presentations will not be allowed during the hearing.

On the second day, ODAC will discuss and issue its recommendations to Hamburg, who will ultimately decide whether Avastin's accelerated approval status will be revoked or maintained.

During the Avastin kerfuffle, Genentech has been reticent in discussing whether a pharmacogenomics strategy would feature prominently in its attempts to convince the agency to maintain the drug's availability in a subpopulation of patients who are best responders. Only after FDA moved to revoke the drug's approval in December did Genentech propose that it would be willing to conduct a randomized, double blind study with a "biomarker component" to identify best responders to the drug (PGx Reporter 01/26/11).

However, when asked this week whether Genentech planned to discuss biomarker analysis involving Avastin at the public hearing, a company spokesperson said that the topics to be discussed at the meeting are laid out in the appeal Genentech submitted to the FDA in response to its decision to revoke Avastin's approval. The appeal, submitted to the FDA in January provides an "overview of the data, analyses, and information that Genentech will review with the FDA at the hearing," a Genentech spokesperson said.

Still, there is a chance that the PGx data discussed in the appeal may not come up during the meeting. "We can't speculate at this time on what will be discussed at the hearing," the spokesperson added.

In its appeal, Genentech does suggest the possibility of identifying best responders to Avastin by conducing biomarker analysis. Previously, the company has used ELISA-based assays to gauge VEGF levels in patients treated with the drug. Clinical trial data suggests that patients with high levels of plasma VEGF-A who received standard doses of Avastin may be more likely to see increases in progression-free survival compared to those with low levels of VEGF-A. However, it remains to be seen if FDA will accept PFS endpoints for a PGx trial.

At a recent ODAC hearing to discuss ways to improve the accelerated approval process for cancer drugs, the FDA and committee members were not impressed that even after genetically stratifying patients in clinical trials, Amgen's colorectal cancer drug Vectibix improved PFS by between two to four months compared to standard treatments. As such, Amgen is now planning to conduct a PGx study to try to show that Vectibix does improve overall survival in patients (PGx Reporter 02/09/11).

Additionally, in challenging FDA's decision on Avastin, Genentech had charged that ODAC members who initially reviewed Avastin's accelerated approval status had "modest expertise" in breast cancer, and asserted that at a public hearing the "FDA and the public would benefit from an advisory committee with greater experience in the specific disease state at issue."

In the letter addressed to both Genentech and FDA's lawyers, agency officer Karen Midthun refused to add breast cancer experts as consultants to ODAC, because such experts are likely to have conflicts of interest with Genentech or its competitors, and the process of picking experts would become "the subject of dispute between the parties."

As such, Midthun wrote that although "Genentech has argued that the committee does not have appropriate expertise to address this issue, we do not interpret FDA regulations as contemplating the substitution of a different advisory committee, and we do not intend to do so."

Genentech markets Avastin in combination with paclitaxel in patients with HER2-negative metastatic breast cancer who have not yet received chemotherapy for metastatic disease. The drug is not approved for people who have received prior anthracyclines and taxanes for their HER2-negative metastatic breast cancer.


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