Early this afternoon the Oncologic Drugs Advisory Committee (ODAC) of the FDA unanimously voted to withdraw its approval for Roche/Genentech’s Avastin® (bevacizumab) for the treatment of breast cancer. The panel's decision will now be taken under consideration by FDA Commissioner Margaret Hamburg, MD, who can either support the committee’s vote or reject it in a final ruling.
The committee specifically voted on whether or not Avastin is (1) safe, (2) effective, and (3) upheld in the treatment of metastatic breast cancer
The answer was an unequivocal no.
The process has not always been easy to understand.
First, there was the issue of accelerated approval, granted by the FDA in February 2008. In a proposal submitted by ODAC and Genentech, "progression-free survival" (PFS) instead of "overall survival" (OS) was introduced as a primary (my emphasis) end point in the use of Avastin in combination with paclitaxel for the treatment of locally recurrent or metastatic HER2-negative breast cancer.
That decision in and of itself was controversial, with committee members voting 5 to 4 for the accelerated approval.
Accelerated approval was based on one study, E2100, which, surprisingly enough, was not "originally designed for FDA approval." In that study Avastin added to paclitaxel resulted in a 5.5 month progression-free survival.
But a number of factors seem muddy now, including the fact that the trial was "open label," where no additional information on concurrent medications is gathered. According to an editorial in the New England Journal of Medicine, both safety and toxicity profiles were incomplete "...since there was no required collection of data on serious adverse events in the control group."
This doesn't make sense to me.
Then, as part of the accelerated process, Genentech was then obligated to pay (support) for additional studies to further demonstrate the clinical benefits of adding Avastin.
In 2009 preliminary data announced at the ASCO Annual Meeting resulted in glowing news reports that one of the studies, RIBBON-1, showed a significant improvement in progression-free survival and confirmed that bevacizumab could be an important component of initial chemotherapy for metastatic HER2-negative breast cancer.
Not only did two different trials fail to reproduce the original 5.5 month difference but serious, significant side effects were reported.
By last summer the committee unanimously voted (12 to 1) to remove treatment for breast cancer from the Avastin label.
When the FDA announced its plan to withdraw approval in December Genentech appealed. This brings us to the hearings that have taken place for the past few days.
Live hearing reports from J. Leonard Lichtenfeld, MD -- @DrLen -- of the American Cancer Society via Twitter and his signature blog posts have been terrific. Since then Sally Church (@MaverickNY) put up a blog post with a wonderful list of resources, and this morning Katie Ford Hall (@uneasypink) posted a helpful explanation of PFS and OS to help survivors better understand this issue.
There is no doubt that this isn’t the last of the discussion.
But I deviate from what others can explain far better than I. At the end of this day, all things considered, I now have more questions than answers:
How did this get off the ground and stay there? While I understand accelerated approval based on very positive findings, I don’t understand that when the trial on which that approval is based wasn’t intended for FDA approval in the first place. Am I missing something here? So the committee – nine people – put into motion the addition of Avastin to chemotherapy based on a trial that wasn’t about drug approval. OK. And that accelerated approval was granted without verifying both safety and efficacy in the first place. Someone explain to me in very simple terms why this was a good thing. I sincerely want to know.
The money issue. Others have written that the ultimate decision wasn’t about the cost of the treatment. I agree there. That is a moot point in comparison with the evidence presented. But isn’t it very much about the money when a pharmaceutical giant undertakes (funds) an accelerated approval process for a drug that brings in something like $6 billion a year. Is anyone talking about this piece of the puzzle? We all know that none of this heartbreak would be taking place if we were talking about soy beans, for example, or aspirin.
Yesterday I tweeted three different take-aways from the hearings that still hold:
-- We need to separate testimony from evidence, no matter how painful;
-- We need to face the difficult truth about metastatic breast cancer and the need for treatments that prolong live with a low-risk profile and,
-- Learning about (and identifying) the subset of women that Avastin HAS helped. Can a specific biomarker be identified and explained so others can be helped? I trust Genentech/NCI is studying them? I do so hope.
In the final analysis it is impossible to write about this without thinking of my friends with metastatic breast cancer, and friends whose lives I still mourn. They are the people I serve. They deserve better than this.
People with cancer deserve better…better science, better safety profiles, better clinical trial design.
It wasn’t even a month ago that I sat in Chicago when the results of Phase III trials completely turned over earlier, positive results in a proposed treatment of triple-negative breast cancer. Here we go again, I thought, watching the Twitter stream both yesterday and today.
It also makes me angry. We can be dispassionate about data, yes, but not about the toll that data represents to women with metastatic disease.
Much went wrong here. We all need to be cognizant of the pressure in every sector of the cancer arena, from the pain of patients and their families to the constant tick of Wall Street to the desire of any scientist/researcher/physician compelled to help their patient.
And in all of us: the ambition to be first…the first to publish, receive the most innovative treatments, the one to find the holy grail unwinding cancer’s mysteries. All of us need to understand the pressures and go back to the drawing board.
I well remember the work of Judah Folkman in angiogenesis and my “wow” moment of hope reading about him. I still maintain that hope, even though these current events and the continued suffering of women with metastatic illness kicks it repeatedly.
I can deal with that. We need to work through the tears and rise above them. And do better. We must do better.