We Will Pay for Avastin

July 1, 2011
By

The following appeared yesterday in The Fiscal Times:

How much should you, your insurer or the government pay for an extra month of life? How much is an extra month of hope worth, even if doesn’t extend life?

Those questions never came up during this week’s Food and Drug Administration appeal hearing on the agency’s decision to withdraw approval from the Roche-Genentech drug Avastin for advanced metastatic breast cancer. But they will be front and center in the years ahead as medical science and the drug industry continue to bring advanced cancer therapeutics to market that have only marginal effects on a devastating disease that takes half million lives a year, most of whom are elderly and receive treatment through Medicare.

The FDA is not allowed to consider costs, only benefits and risks, when deciding whether to approve or withdraw approval for drugs or other medical devices. Yet cost was clearly the backdrop as the FDA’s Oncology Drugs Advisory Committee on Wednesday voted 6-0 to reaffirm last December’s FDA decision to withdraw approval for the $88,000-a-year drug, which only stops breast tumors from progressing for a few months and doesn’t extend life. Genentech had appealed the decision. FDA Commissioner Margaret Hamburg will make the final determination sometime later this year.

Avastin, one of the new targeted therapies that a decade ago were heralded as a major advance in cancer therapeutics, has turned out to be much less effective than originally hoped. Although it has been approved for colon and lung cancer, its effects on those common cancers are also limited.

In 2008, the FDA granted Avastin so-called “accelerated approval” for metastatic breast cancer based on a single clinical trial showing the drug, when combined with standard chemotherapy, delayed tumor progression by 5 ½ months compared to chemo alone. There was also a hint that it might prolong life.

The accelerated approval program, which was created in the early 1990s as a way of rushing promising AIDS drugs to market, requires companies to conduct additional clinical trials to confirm the promise shown in the earlier test. However, when the new trials came in last year, they not only didn’t show any increase in overall survival, they failed to fully replicate the delay in tumor progression seen in the original trial.

That scientific evidence was of little interest to the dozens of breast cancer patients, their families, physicians and advocacy groups who showed up at the hearing to offer emotional testimony in favor of the drug. Shannon Morgan of Charlotte, N.C., who has survived a diagnosis of metastatic breast cancer for over two years, insists she is alive today because she was treated with Avastin (the median time of survival in the original trial was 24.8 months on chemotherapy alone, compared to 26.5 months on chemo plus Avastin; statistically there was no difference, meaning the results could have been by chance). She’s afraid her insurance company will stop paying for the drug if the FDA withdraws approval

“You may be rich but I am not,” she testified. “If you take Avastin for breast cancer off the label, how many of us successful users will die during that time? Do you want that on your conscience?”

The fears and hopes of patients like Morgan lie at the heart of the nation’s emerging struggle with the rising cost of cancer care, which is one of the major drivers of rising Medicare costs. A study that appeared earlier this year in the Journal of the National Cancer Institute estimated the U.S. paid about $125 billion for treating the 16 most common forms of cancer in 2010. By 2020, that tab is likely to grow to $173 billion because of the aging of the population and the rising cost of new drugs and other therapeutics.

But so far patient fears that the government or insurance companies might ration care by using cost-benefit analysis like Great Britain’s National Institute for Clinical Excellence has not come to pass. Medicare and most insurers continue to pay for any drug listed in guidelines written by the National Comprehensive Cancer Network, an alliance of the nation’s largest academic cancer centers.

In the wake of the FDA’s announcement last December that it planned to remove the breast cancer indication from Avastin’s label, NCCN announced it wouldn’t follow suit. Many oncologists who use the guidelines insist the drug provides improved quality of life for their patients, since every month the tumor doesn’t progress is a month they can continue believing they may defeat the disease. They can continue to prescribe Avastin for breast cancer patients “off label” since it is still available for other indications. In addition, 11 of the 33 physicians on the NCCN breast cancer guideline writing panel have financial ties to Genentech, including the committee’s chairman Robert Carlson of Stanford.

“If the NCCN recommends it, regardless of what the FDA does, we wouldn’t make any changes,” said Lee Newcomer, senior vice president for oncology at UnitedHealthcare, the nation’s largest private insurer with 25 million covered lives. “We have lots of off-label indications from the NCCN that we pay for. We wanted to have those decisions made outside the company to avoid any impression that we would deny drugs simply for costs.”

But that precludes insurers like United from bargaining for a lower price based on the drug or other intervention’s limited efficacy. “We are bound to cover an FDA-approved drug by insurance regulators and at United, by our own policy, we are bound to use NCCN recommendations,” Newcomer said. “The manufacturer is well aware of that. They know we have no leverage at the negotiating table. Whatever price they set, we’re forced to pay.” The same is true for Medicare.

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6 Responses to We Will Pay for Avastin

  1. Elaine Schattner on July 1, 2011 at 5:02 am

    Merrill, I understand the statistics.

    But what about the women who fit into the tail end of the curve, who have aggressive, triple negative BC, who have responded to Avastin and no other drug. What if they happen to have really knowledgeable BC oncologists (none was on the panel, as you know), the sort who wouldn’t continue to give the drug if it weren’t clearly helping and not hurting?

    You’re right about Medicare, and there being insufficient funds, but I don’t think the fix is in denying medicines that are working in particular cases, especially to people who are so young.

    There are zillions (no), but probably billions of dollars that could be saved by not putting terminal cancer patients on ventilators, or by not giving aggressive treatments to people who are severely demented or have been in comas for years, but no one would dare pull support for their life-sustaining treatments. Why pull the plug on middle-aged BC patients who are responding and capable of giving informed consent?

    • GoozNews on July 1, 2011 at 2:20 pm

      I thought a lot about this question as I sat through the hearing. So here’s the question: how do we know the women on the “tail end of the curve” are there because of Avastin? They were randomized to either receive the drug or not. Some of the ones who received the drug and lived longer showed up to insist the drug was the reason why. But what about the women in the placebo arm of the trial who were also on the “tail end of the curve”? Don’t forget: The two Kaplan-Meier curves (this tracks the number of women still alive at any point in time) were nearly identical. Alas, nobody shows up at these hearings to report that they lived longer on placebo.

  2. Chris Lovell on July 1, 2011 at 8:46 am

    Interesting article about the ramifications of FDA withdrawal of approval for Avastin for breast cancer. I think this situation will eventually start to change the US approach to chemotherapy treatment simply because we are not using science to determine decisions right now especially in areas with strong activist groups. Can anyone remember the demand for bone marrow transplant for breast cancer even though there was no evidence it would work. Lots of women went through useless painful and expensive treatment for no gain.

    This situation will also probably reduce the fast approval process because the FDA is now faced with trying to close the bottle now the genie is out.

    • Greg Pawelski on July 2, 2011 at 8:29 am

      In the 90′s, we were subjected to bigger guns, more firepower with high dose chemotherapy and stem cell transplant, costing as much as $250,000. More is not always better. You give more aggressive chemotherapy (i.e. combinations, high dose therapy, whatever) in diseases like metastatic breast cancer you increase response rates, but you don’t improve overall survival.

      In a review of 15 randomized high-dose chemotherapy and autologous stem cell transplantation studies conducted around the world between 1988 and 2002, investigators from MD Anderson reported that while there was a slight benefit on relapse-free survival, there was no benefit to overall survival. Ineffective, aggressive chemotherapy can diminish not just quality of life but also quantity of life, through organ toxicity, immunosuppression, and/or by inducing mutations in genetically unstable tumor cells to more aggressive phenotypes.

      However, the same researchers from MD Anderson are still doing high-dose chemo and autologous and allogenic stem cell transplants for ovarian cancer. Their new study involves Avastin and an allogenic stem cell transplant. The theory is that the donor stem cells will create a graph verses tumor effect where by the donor stem cells will recognize and fight the cancer where the patients own immune system has failed.

      This type of stem cell transplant is a standard treatment for Leukemia and now they are trying it with solid tumor cancers. Do you think that this is a crazy idea just like the autologous stem cell transplant? Why do you think MD Anderson continues to do these stem cell transplant clinical trials if they don’t seem to improve outcomes? Is the allogenic stem cell transplant that much more effective (theoretically) than autologous stem cell transplant?

  3. Greg Pawelski on July 1, 2011 at 11:39 am

    Merrill, you bring up the issue that the Avastin situation maybe a drawback to the “Accelerated Approval” process. Perhaps this is a drawback to the clinical trial system, a scientifically bankrupt paradigm which has not fostered either efficient or humane progress in cancer chemotherapy.

    The problem is not with using the prospective, randomized trial as a research instrument, the problem comes from applying this time and resource-consuming instrument to address hypotheses of trivial importance: do cancers prefer Coke or Pepsi?

    It is recognized that the benefits of Avastin overall are modest for women with metastatic breast cancer, and that it is known that for some women, Avastin offers a greater than modest benefit. Just who are those who benefit?

    The VEGF (vascular endothelial growth factor) system is a target for a number of anti-microvascular cancer drugs. Avastin (bevacizumab) can block VEGF and cause existing microcapillaries to die. But it’s not the only drug that can do this.

    Many conventional chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. The anti-angiogenic effects of therapy are masked and marginalized by the way it is usually administered. There are generally long breaks between drug administration that are necessary to allow the patient to recover from the harmful side effects of treatment.

    When administering these drugs, the endothelial cells (involved in angiogenesis) are the first in the tumor to undergo cell death (apoptosis). However, this anti-angiogenic effect does not translate into a significant therapeutic benefit because the damage to the vasculature of the tumor can be largely repaired during the long rest and recovery periods between successive cycles of therapy.

    The more frequent, lower-dose therapy can have an impressive anti-angiogenic and anti-tumor effects. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

    The main targets of dose-intensive chemotherapy are proliferating tumor cells. The main targets of low-dose chemotherapy are the endothelial cells of the growing vasculature of a tumor. In other words, chemotherapeutics can be used as anti-angiogenic agents.

    And a lot of those chemotherapeutics are much less costly than Avastin. It’s not a case of more costly drugs vs less costly drugs, it may be a case of technique (finesse).

  4. Mutuelle Entreprise on July 5, 2011 at 5:26 am

    In France, the health system is more favorable to patients.
    the state supports 70% of overall medical costs (consultations, hospitalization, medication) 30% shall be borne by the patient or health insurance.
    The health system is in deficit, but efforts are being made to achieve financial balance (note the abuse).
    Health insurance more accessible to French

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