Roche Suggests A Compromise Over Avastin
6 CommentsBy Ed Silverman // August 8th, 2011 // 12:24 pm
In a bid to salvage the breast cancer indication for Avastin, Roche’s Genentech unit has pitched to the FDA what it is calling a “middle-ground proposal” that would allow the drug to retain its indication and only for use with paclitaxel. The deal includes revised labeling in which Avastin would be recommended only for patients displaying “aggressive disease” and who have the fewest treatment options. Roche also suggests a Risk Evaluation and Mitigation Strategy, or REMS, as well as a Medication Guide.
The move comes just a few weeks after the completion of an extraordinary, two-day FDA advisory committee hearing in which panelists voted 6-to-0 to pull the breast cancer indication for Avastin. The drugmaker had appealed a decision last December by the agency to yank the indication, prompting a heated debate over the veracity of the FDA accelerated approval program (see here and here).
In explaining their initial decision, the FDA cited results of clinical studies and determined the data indicate Avastin does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh significant risks. These include severe high blood pressure; bleeding and hemorrhage; development of perforations in the body, including in the nose, stomach, and intestines; swelling of the brain, and heart attack or heart failure.
But Avastin is important to Roche. Many oncologists may continue to turn to Avastin as a salve, given that the Medicare is likely to continue coverage and the National Cancer Comprehensive Network has maintained its endorsement (read this, this and this), but the drugmaker stands to lose some $1 billion in annual sales if the FDA does pull the indication and doctors turn elsewhere for treatment.
“Retaining accelerated approval will allow Avastin to remain available to the patients who have the greatest unmet need, while Genentech addresses (FDA) views regarding Avastin in metastatic breast cancer by: (1) conducting a confirmatory trial of Avastin with weekly paclitaxel’ (2) adopting labeling to direct doctors to the most appropriate MBC cases; and (3) undertaking further physician and patient communications to emphasize the efficacy and safety data, thus supporting informed decision making regarding Avastin,” the drugmaker writes in its 133-page proposal.
“Two facts cannot be disputed in the wake of the hearing to withdraw Avastin’s breast cancer indication: the approved treatment options for patients with metastatic breast cancer are extremely limited, particularly for patients who face aggressive disease; and Avastin in combination with weekly paclitaxel indisputably has an effect on this form of breast cancer. These facts drive Genentech’s proposal to retain accelerated approval for Avastin plus paclitaxel, subject to a confirmatory study and with revised labeling and risk communications that respond directly to the views CDER has expressed regarding Avastin,” Roche concludes (read the complete proposal here).
original industry insider
To me this is another nail in the coffin for accelerated approval. If the Avastin breast cancer NDA program had gone through the FDA regular review cycle (non fast tracked), and Genentech were given a CRL non-approvable type letter, there then would likely have undergone the standard back and forth negotiation process with the agency. IMO the likely outcome of that process may well have been a limited approval label, allowing use of Avastin in combination with paclitaxel. This would have saved face for the company, the FDA, and insurers in a single stroke.
Now Genentech is trying to arrive at the same ending but doing it after the horse is out of the barn. I predict the FDA will not compromise, but let’s wait and see. The morale of the story in hindsight is that Genentech could have had its cake and more if it originally had the patience to go through the standard review cycle.
Not-so-original industry insider
While always easier to critique someone else’s comment than generate your own, I feel compelled to note that the comment above is simply . . . .well, simplistic. In fact, arm-chair quarterback at its finest. If you are on the heels of an approval in breast cancer with a Phase 3 study, I don’t know if there is a board in the world that says, “Hold on, we think that the fast-track approval process doesn’t make sense.”
That said, I do wholeheartedly agree that accelerated approval is a flawed process and one which has resulted in a black eye for all involved, Genentech, MDs and the FDA alike. My biggest hope, for the sake of patients, is that the FDA strongly consider the stance that OS is a requirement for approval in FL MBC, to me a risky criteria that doesn’t take into consideration the realities that exist today in the treatment of BC.
Greg Pawelski
Oh good God! What a fricken compromise! Avastin only with paclitaxel (Taxol)? In an NCI Cancer Bulletin on February 8, 2011 (Volume 8 / Number 3), it stated that when combined with Taxol, Avastin is associated with a 3-fold risk of death. Cancer patients who receive the targeted therapy Avastin in combination with taxane therapy are at increased risk of serious side effects that may lead to death, according to a meta-analysis of 16 clinical trials that was conducted by researchers at Stony Brook University School of Medicine in New York. The results were published February 2, 2011 in JAMA.
Adding Avastin, which only goes after VEGF-sensitive cancer cells, you need to go after other pro-angiogenic factors which can substitute for VEGF: FGF, PDGF, ephrin A1, angioprotein 1, IL-8, etc. And with Taxol promoting an increase of IL-8, how effective is it with Avastin? With Taxol increasing the production of a cellular communication molecule that initiates growth of new blood vessels to feed a growing cancer, Taxol is worse off than anyone has ever realized (highly resistant, initiates cancer blood vessel growth, increases circulating tumor cells, and not the least, very toxic). No wonder they want to add Avastin to the mix!
Like Little Richard sang, “Good Golly Miss Molly!”
original industry insider
NSOII, that is precisely the problem, as you suggest. Pressure from the Board to seek fast track approval will surely bump up the stock price in the short term, but when quarterly profits outweigh the potential long term benefits for patients, and possibly even for shareholders, such exuberence may become irrational.
IMO, fast track approval should be sought ONLY when two conditons are met: 1) the short term data are solid, AND 2) the short term data give some predictability of long term success. Example, when I worked on NDA’s for HIV drugs, it was standard to seek approval after 24 weeks based on solid, reliable and predictable changes in gold standard markers, namely t-cell counts and viral RNA load. The vast majority of the time, based on the 24 week data, there was at least 95% probability of success that those markers would hold up successfully after 48 weeks, and they pretty much did just that if you look at th track record across multiple submissions from multiple companies.
Therefore, I ask, is it too much to hold oncology drugs to the same high standards of fast track approval? BTW, Roche, the maker of Avastin was one such company, and there was no pressure as I was aware of from my Roche friends to submit flimsy 24 week data just to please the board. Also the HIV drug developers were under just as much pressure from advocacy groups as the Avastin developers.
Not-so-original industry insider
OII, I too agree that the highest standards should be applied to oncology drugs and oncology drug development, no question or argument here at all. I think you forward very interesting and reasonable conditions for FT approval. I think it only fair, thought to remember the context in which decisions at the time were made. See the quote below in a Medscape article post-ASCO 2005:
“These findings are exciting because this is the first time an antiangiogenic agent has been found to be successful in breast cancer,” said Gabriel N Hortobagyi, MD, in an interview seeking outside comment.” Dr. Hortobagyi is the president-elect of ASCO and the chair of the breast medical oncology department at the University of Texas M. D. Anderson Cancer Center in Houston. “It is one of the few agents that has been proven to prolong survival in metastatic disease.” Dr. Hortobagyi added that the adverse events, particularly the potential for cardiovascular events, needed to be carefully monitored, but pointed out the benefits clearly outweighed the risks.”
Obviously part of this was wrong, the OS part, but when the President of ASCO says the drug works, well . . . .the decision doesn’t seem to me to be one of “impatience” nearly as much as a sense of urgency.
Full article:http://www.medscape.com/viewarticle/505141
original industry insider
Thanks, NSOII and Greg. In the HIV arena, the surrogate markers I referred to, t-cell counts and viral RNA didn’t just happen overnight. The were the products of many years of trying to understand the the Human Immunodeficiency Virus, how it worked its damage on the body’s immune system, and it was only then that we were able to understand what were the best surrogate markers for predicting disease progression and response to treatment.
On the other hand there seems to be a great burst of enthusiasm whenever a new oncology drug comes along that is a putative treatment for a disease mechanism (e.g. angiogenesis) whose pathologic and prognostic significance is unknown. To make it short, what do know about the importance of angiogenesis to tumor progesssion and disease survival in the first place? It therefore logically raises the question: ff we don’t know the significance of angiogenesis in the first place, how can we rely on antiangiogenesis drugs for efficacy?
If the oncology field can come up with the same reliable surrogates that I’ve cited above for HIV then I would have no problem with fast track approval of these agents. Until then I remain skeptical.