For those of you who have been following this blog you will recall that I have spent a lot of time discussing cancer drug costs and the lack of any real control that CMS (Medicare) or private insurers have on determining what cancer drugs they will cover – regardless of their price. Although I have focused on Provenge®, which as predicted had a positive NCA hearing in November, the FDA withdrawal process of the Avastin breast cancer indication has also been very illustrative.
As many of you are probably aware, Avastin failed to show a survival benefit in 4 large randomized metastatic breast cancer studies: E2100, AVADO, RIBBON-1 and AVF2119g. The FDA issued a statement on December 16th recommending withdrawal of the breast cancer indication - “the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients”(1). Genentech has indicated it will not voluntarily withdraw the indication and has asked for a hearing to present their rational for maintaining the indication. The debate concerns the fact that despite failing to demonstrate a survival benefit, a statistically significant improvement in progression-free survival (PFS) was observed in the studies. PFS essentially measures the duration of time a patient is in remission. The FDA considers overall survival (OS), which is the time until a patient dies, to be the “gold-standard” end-point for oncology drugs. Although many consider PFS to be a predictor of OS and patient benefit, it is prone to errors due to the subjective manner by which it is measured. Observing an OS benefit can also be difficult when testing a first-line treatment due to the influence of second and third line treatments that patients receive. My guess is that Genentech will argue that OS is not a feasible endpoint in first line metastatic breast cancer and that the results were confounded by 2nd and 3rd line treatment effects. Although this may be true, it does not change the fact that patients did not live longer - the benefit from Avastin was not sufficient to make a measurable difference and patients are at risk of side-effects. I predict that the FDA will withdraw the indication.
The fall-out from the FDA statement recommending withdrawal has been very interesting to say the least. In December the NCCN published an update to its breast cancer guidelines and compendia listing and remarkably its panel of experts decided unanimously to maintain usage of Avastin in breast cancer as a listed indication (evidence level 2A, 15-0 vote in favor) (2) . Remarkable, because this panel of experts came to a completely different conclusion than the independent FDA panel of experts. I suspect that the NCCN panel has a more “real-world” understanding of the impact of removing the indication and believe that an improvement in PFS is an important patient benefit. On the other side of the fence Palmetto GBA - a Medicare carrier and Regence BCBS - a private insurer, announced they would no longer cover Avastin in Breast cancer (3,4) .
You will re-call from my blog in October that CMS (and its carriers) and most private insurers are required by law to cover compendia listed indications regardless of whether or not they are approved by the FDA. As a Medicare Carrier Palmetto must adhere to this law, someone must have called them (perhaps a lawyer?) and remind them of this and the fact that the indication has not officially been withdrawn yet because the following day Palmetto redacted its announcement withdrawing coverage3 - ooops. Regence BCBS operates in Oregon which has a law that gives the state the ability to mandate coverage of compendia listed indications by an insurer if the insurer has denied coverage soley because of the absence of an FDA indication. I contacted Regence and they explained that their withdrawal was based on their determination that Avastin is not medically necessary for the treatment of breast cancer and so withdrawal of the FDA indication will not be their sole reason for denying coverage. This loophole makes the Oregon law mandating coverage of compendia listed off-label indications easy to bypass and ineffective. The state laws mandating private payer coverage of compendia listed indications apply to approximately 75% of the US population (5). Unfortunately, as the Oregon law demonstrates, they vary in their effectiveness. It will be interesting to watch and see whether other state laws will be able to maintain private payer coverage of Avastin when it officially becomes an “off-label” indication.
5. The Rising Price of New Oncology Drugs. Source: Peter B. Bach, M.D., M.A.P.P. N Engl J Med. 2009;360:626-633
The internet has lit up with stories on the subject from patient advocacy groups and even the right-right-wing tea folks like Rush Limbaugh. Understandably, the patient groups are demanding that the indication be maintained so that patients who are currently benefitting from Avastin can continue receiving it and maintain their insurance coverage. Interestingly, the National Breast Cancer Coalition has sided with FDA and noted that “we need to focus advocacy, public policy and resources on saving lives and doing more good than harm” (6). The right-right-wing types, including Rush Limbaugh, are pointing to the withdrawal of the indication as the first step in the enactment of Obamacare “death-panels” (7). Wow – they really do like to scare people with misinformation. There was not a conspiracy by the government to influence the independent FDA panel that reviewed the data last July nor will most patients be losing their insurance coverage. The fact remains that with-out a change in federal and state law, the compendia listing really controls what cancer drug indications are covered by CMS (Medicare) and most 3rd party private payers respectively. Is that a good thing? Probably. It keeps the decision about treatment in the hands of the patient and physician while improving care by eliminating the “cowboy” use of drugs for indications where no data exists. Although, the tax and health insurance payer in me does wonder how we will be able to pay for it over the long term. This issue illustrates the political conundrum in our country today. Coverage of clinically proven cancer drug indications are a necessity, we must be prepared to pay for them or find ways to control their costs so that they remain affordable. I will leave that subject to another blog…
Because of the high volume of traffic on the blog we have added a few interview quotes related to the Avastin topic that we have from the San Antonio Breast Cancer Symposium.
These comments, made prior to the FDA’s recommendation to withdraw the Avastin indication, were taken from OBR interviews conducted at SABC:
I mean the big elephant in the room is the cost. If this drug was completely affordable you would not be asking me about Avastin – nobody talks about it, but that’s the problem. Further, detractors or proponents agree that we have not a good job in developing biomarkers, or tests that will tell you in what patients you should or should not use Avastin.
Carlos L. Arteaga, M.D.
Donna S. Hall Chair in Breast Cancer Professor of Medicine and Cancer Biology Interim Director, Division of Hematology/Oncology
Vanderbilt-Ingram Cancer Center
Vanderbilt University, Nashville, TN
The FDA is not immune from politics and they are not also immune from the legal constraints in which they operate. I still consult with the FDA, and I’ve been on the ODAC, so I have a little experience, a little appreciation that they don’t live in a vacuum.
John T. Carpenter, MD
Professor, Hematology & Oncology
University of Alabama at Birmingham
I do generally give bevacizumab when I’m starting my first line chemo – I haven’t changed that because I don’t really believe that the weekly paclitaxel/bevacizumab data has fallen apart. I am disappointed though that RIBBON 1 and 2 trials, and AVADO, although positive, weren’t stronger, but the FDA reversing the label for breast would be unprecedented, and in my mind unwarranted.
Julie Gralow, MD
Clinical Research Division, Associate Member, Fred Hutchinson Cancer Research Center; Oncology Specialist, Professor, Medical Oncology Division
University of Washington School of Medicine, Seattle
I think that certain patients do indeed benefit, and I think that part of the differences in trials may just be that the type of chemotherapy that is combined with bevacizumab actually matters, and maybe weekly taxanes are really the best pair for bevacizumab. …the question is how to best identify what drug to pair with bevacizumab in breast cancer, and what is the best patient.
Alberto Montero, M.D.
Assistant Professor of Medicine
Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, Miami
I think among the breast cancer community, we would love to continue to be able to use this agent, and do feel that it is an active agent that met its primary endpoint in three well conducted, large randomized Phase III trials. It could be withdrawn, of course, and if that happens, I don’t think anyone in the breast cancer community thinks that that’s a scientific decision, but a decision based more on politics and economics.
Erica L. Mayer, M.D.
Instructor, Department of Medicine, Harvard Medical School
Director, Clinical Research (Faulkner Hospital), Dana-Farber Cancer Institute
David is a veteran of the cancer business with 15+ years of experience commercializing several well known oncology therapeutics. He is currently a consultant and lives in San Diego. Please send your questions and comments to email@example.com.
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