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Genentech's Avastin Goes to FDA Panel


This is history vs. politics, so both Hoofy & Boo should beware...


In December, Genentech (DNA) "gets" to go in front of the FDA's Oncologic Drugs Advisory Committee (ODAC) for a review of Avastin in breast cancer. Avastin is already approved in the EU for this indication.

In May 2006, Genentech submitted data from the "E2100" pivotal trial in breast cancer patients who had been treated previously for breast cancer with surgery or radiation, but not chemotherapy. The 722-patient trial demonstrated a statistically-significant advantage in progression-free survival (PFS) for Avastin plus chemotherapy versus chemotherapy alone. However, there was no statistically-significant benefit seen in overall survival.

The FDA kicked the application back to Genentech, claiming there were issues with how the scans were read to determine PFS. It was broadly acknowledged in biotech circles that the FDA kicked the application back hoping the overall survival data would mature to be statistically significant.

DNA re-submitted its application for approval in August. Overall survival is still not statistically significant. The FDA set a PDUFA (decision deadline) date of February 23, 2008 and scheduled an ODAC panel meeting for December.

Richard Pazdur is the head of the FDA's Office of Oncologic Drugs (OOD) and the guy who constructs the ODAC panel. You've read consistent criticism of Dr. Pazdur from me as I think he makes it far too hard to get cancer drugs approved. He's a perfectionist in charge of a healthcare segment where perfection is impossible. He relies on strict biostatistical interpretations of clinical data to the exclusion of clinical common sense. The end result is patients and their families suffering needlessly.

A legitimate question for breast cancer patients is why the FDA is hesitating when the EU already approved Avastin based upon these data. The answer requires an understanding of how the OOD under Pazdur has devolved via an overreliance on biostatistics.

Under current management, OOD believes the only appropriate endpoint for an oncology drug is survival. If the drug does not increase survival, then it is not worthy of approval. Approval on other metrics is possible, however, under the Accelerated Approval guidelines. Created by Congress in the late 1990s, this allows for drug approval based upon surrogate endpoints.

In terms of modern oncology drug approvals, a surrogate endpoint is a clinical endpoint likely to predict an overall survival benefit. A preferred surrogate endpoint under current OOD behavior is PFS.

The problem with Avastin is the trial did meet the PFS endpoint, but failed to meet the overall survival secondary endpoint. This calls into question the idea that PFS is "likely to predict an overall survival benefit." This contradiction in the data is why Dr. Pazdur wants ODAC review.

There is some precedent for this in ODAC panel meetings in the current modern age (roughly 2004 forward). Some you have to take with a grain of salt because there were other things going with the applications. You also have to factor in that Dr. Pazdur is biased towards large companies, knowing their fleets of lawyers and political connections are more likely to enforce consequences when he wields his brand of regulatory power.

In May 2004, Genta (GNTA) brought its drug Genasense to ODAC for approval in melanoma. The drug demonstrated statistically-significant benefits in secondary endpoints of PFS and overall response (tumor shrinkage, or ORR), but failed the primary endpoint of survival. All other melanoma drugs approved prior to that meeting were based on PFS, ORR, or improvement in quality of life. Despite this, Genasense was turned down for missing the primary endpoint. One contributing factor to this decision was Dr. Pazdur's removal of all melanoma experts from the ODAC panel – except for an employee of a competitive firm.

In 2006, Genta brought Genasense to ODAC again – this time for the blood cancer CLL. The drug met its primary endpoint of complete responses (CRs), but did not see a survival benefit. Despite no CLL drug ever having survival data at the time of approval, and despite the broad backing of the expert CLL community, ODAC turned the drug down. Again, Dr. Pazdur removed all CLL experts from the panel except for the industry representative to the panel, who was barred from speaking during the vote by ODAC chair Dr. Maha Hussain.

In 2007, Dendreon (DNDN) brought Provenge to a different FDA panel, securing a 13-4 vote that the data was sufficient to demonstrate efficacy and a 17-0 vote that the data demonstrated the drug was safe. Dr. Pazdur led a fight within the FDA that ultimately succeeded in causing Provenge to be turned back. This decision was based upon the argument that while Provenge demonstrated a survival benefit, it did not demonstrate a benefit on the primary endpoint of the study – time to tumor progression (TTP). TTP was a common approvable endpoint in oncology studies in the late 1990s when the Provenge trials were designed, but has since been discounted as an appropriate endpoint – particularly by ODAC who favors survival as the only approvable endpoint in prostate cancer.

In 2007, GPC Biotech (GPCB) brought satraplatin to the FDA. This prostate cancer drug demonstrated a highly statistically significant benefit in PFS but survival data were immature and not positive. GPC was asking for accelerated approval. The FDA did not like the way GPC adjudicated the PFS endpoint, something GPC hid from investors. Clearly, however, the drug has a benefit to patients. Nevertheless, ODAC turned the drug back while chastising prostate cancer patient advocates for attempting to convince the FDA to approve the drug.

To sum up, we have these precedents:

  • Rejection of a drug that hit secondary surrogate endpoints but missed survival.

  • Rejection of a drug that hit primary surrogate endpoints but missed survival.

  • Rejection of a drug that hit a secondary survival endpoint but barely missed a primary surrogate endpoint.

  • Rejection of a drug that hit a primary surrogate endpoint but a survival benefit is to be determined.

Genentech is asking for approval on a drug that hit a primary surrogate endpoint, but failed the secondary survival endpoint.

Modern FDA history suggests two conclusions, neither particularly positive for Genentech:

1. ODAC and OOD do not like to approve drugs based upon a surrogate endpoint when survival is not positive.

2. ODAC and OOD do not like to approve drugs when the trial data and biostatistics are not perfect.

My take? Despite this, I think there is almost no chance Avastin is voted down by ODAC. If ODAC says no, I expect Pazdur to overrule them. Avastin is a proven cancer fighter that, importantly, is widely embraced by academic oncologists. Academic oncologists are falling all over themselves to try modern targeted drugs in big new trials and they won't vote against Genentech for fear they will be left off the company's clinical trial gravy train.

Further, I do not believe Pazdur will screw with the breast cancer lobby. He's already under significant fire from an emerging prostate cancer lobby, and won't risk angering the much more connected and wealthy breast cancer groups.

By modern history, ODAC and OOD should reject Avastin. I don't think they will. If you bet long on Genentech into this decision, recognize you're depending on politics winning out over regulatory history. If you bet short on Genentech into this decision, recognize you're depending on history winning out over politics. I think the short side is a bad bet here, but both sides need to keep their eyes open all the way through to the February PDUFA date. The December ODAC panel vote may not be the last, best word on the approval of Avastin for breast cancer.

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