FDA Did the Right Thing in Pulling Avastin for Breast Cancer

(This post originally appeared on Avik's Forbes blog, The Apothecary.)

On Friday, FDA Commissioner Margaret Hamburg announced that the agency was revoking its approval of best-selling cancer drug Avastin for breast cancer. This decision is no surprise, coming on the heels of advice from the agency's panel of outside experts last August, which itself was triggered by Genentech's failed phase III trial of Avastin in breast cancer. I continue to fail to understand why conservatives are up in arms over the FDA's decision. If anything, the way FDA has handled Avastin should be a model for future regulatory decisions.

Avastin's FDA history

First, some background. In 2004, the FDA approved Avastin for first-line treatment of patients with metastatic, or malignant, colorectal cancer. The tremendous success of Avastin turned Genentech from a biotech also-ran into the sector's most-valued company. The drug eventually gained additional approvals for second-line metastatic colorectal cancer (2006); first-line non-small cell lung cancer (2006); metastatic HER2-negative breast cancer (2008); second-line glioblastoma, a form of brain cancer (2009); and metastatic renal cell carcinoma, a form of kidney cancer (2009). The drug's mechanism of action--starving tumors of the blood supply they need to grow--proved effective in a wide variety of cancers, and Avastin became one of the most successful cancer drugs in history.

The FDA takes a leap of faith on Avastin

The 2008 approval in breast cancer was based on encouraging results from a 2005 phase III study, the E2100 study sponsored by the Eastern Cooperative Oncology Group. ECOG-E2100 compared Avastin in combination with Taxol (paclitaxel), an older chemotherapy drug, with Taxol alone. While the ECOG study wasn't blinded--patients knew what treatment they were getting--the study showed that patients on the Avastin-plus-Taxol did better on an endpoint called "progression-free survival," which measures how long patients live without a growth in the size of their tumors. Avastin-plus-Taxol patients had a median PFS of 11.3 months, versus 5.8 months for Taxol.

On the basis of ECOG-E2100, the FDA granted "accelerated approval" to Avastin in breast cancer, despite the fact that the trial wasn't up to traditional FDA standards: it wasn't blinded such that doctors wouldn't know which treatment they were giving, and such that patients wouldn't know which treatment they were receiving (what statisticians call double-blinding). In addition, the FDA strongly prefers not to approve drugs on progression-free survival, which is a somewhat soft endpoint, preferring instead to approve a drug on overall survival: the most objective endpoint there is. (Did you live, or die, after taking the drug?)

The FDA's accelerated approval of Avastin was conditioned on Genentech conducting a proper, double-blinded study comparing Avastin to the standard of care. The study would need to show that patients on Avastin lived longer than those who weren't on Avastin.

The FDA's decision aids biomedical innovation

In other words, the FDA did exactly what I and other FDA-watchers are always asking the agency to do: get drugs out there quickly, put them in the hands of doctors and patients, and let the clinical evidence pile up over time.

The FDA only pulled its approval of Avastin for breast cancer after that blinded phase III trial was finished, a trial that showed that patients on Avastin didn't live longer than those not on it. Because Avastin is already approved for other diseases, doctors are free to prescribe it "off-label" for breast cancer if they want to. Medicare has promised that they will continue to pay for it, even though it's debatable as to whether or not they should.

The Wall Street Journal, and others, have denounced the FDA's move as "a chillingly blunt assertion of regulatory power." But Paul Howard is the guy who gets it right:

If you think (as I do) that the FDA should be expanding the accelerated approval pathway and allow more drugs to get to market based on promising early studies. rather than waiting for large Phase III clinical trials that can take years to complete, you can argue that this outcome actually strengthens AA. Critics have charged that AA is sop to industry, and that companies never do the follow up studies to support AA. Avastin proves them wrong.

This is exactly the point. If you want the FDA to approve more innovative, new drugs based on promising but early clinical results, you have to give the FDA a way to revoke those approvals later on, should larger trials prove that those drugs aren't as safe or effective as they first seemed. This is why the FDA should be congratulated for the way it has handled the Avastin breast cancer saga, and why I hope we will see the FDA handle more cases like this one, not less.

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