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The impact of the Patient Protection and Affordable Care Act (PPACA) will be front and center later this week when the Food and Drug Administration (FDA) decides whether to revoke marketing clearance of the cancer drug Avastin for breast malignancies.
On one side, you have critics of the FDA accusing them of rationing healthcare while on the other side, you have comparative effectiveness research showing that there’s no statistically meaningful difference in the survival of patients receiving Avastin plus chemotherapy compared to chemotherapy alone.
What is Comparative Effectiveness Research?
Traditional clinical research typically evaluates the effectiveness of a single method for preventing, diagnosing or treating health conditions compared to no intervention. Comparative effectiveness research compares two or more different methods. This is done using clinical trial data, analyses of claims records, systematic reviews of biomedical literature or computer modeling.
The aim of comparative effectiveness research is to improve health outcomes by developing evidence-based information on the effectiveness of treatments relative to other options and disseminating that information to patients, providers and healthcare decision-makers.
Over the past decade, there has been some federal funding for comparative effectiveness research, principally through the National Institutes of Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ). Funding was dramatically increased when, in 2009, the American Recovery and Reinvestment Act allocated $1.1 billion for comparative effectiveness research.
The PPACA builds on the economic recovery package to support and direct research comparing patient treatments. The PPACA establishes a new Patient Centered Outcomes Research Institute (PCORI) responsible for the identification, prioritization and execution of comparative effectiveness research.
The issue surrounding Avastin
And that brings us to the issue surrounding the use of Avastin.
Avastin (bevacizumab) is a targeted monoclonal antibody that prevents tumors from creating and maintaining their own blood supply. Tumors can’t grow without oxygen and nutrients from blood. Avastin doesn’t cure cancer; it averts and/or reduces the spread of cancer-causing cells.
Avastin blocks a protein called vascular endothelial growth factor (VEGFA and VEGFB), which plays an important part in the formation of blood vessels, a process called angiogenesis. In addition to metastatic breast cancer, Avastin has also been approved for metastatic colorectal cancer, non-small cell lung cancer, metastatic kidney cancer and glioblastoma.
In 2008, the FDA granted accelerated approval for Avastin to be used in combination with paclitaxel chemotherapy for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer. The approval was based on a phase III study (the E2100 study) of 722 patients with metastatic breast cancer randomly assigned to receive Avastin with paclitaxel chemotherapy or paclitaxel alone. A doubling in progression-free survival was observed in patients who received Avastin in combination with paclitaxel chemotherapy compared to patents who recieved paclitaxel alone .
Note however that this result doesn’t mean that women taking Avastin lived longer. A doubling in progression-free survival simply means that it took twice as long for the tumor to progress. In fact, there was no increase in overall survival. Moreover, those women who received Avastin experienced a higher overall incidence of toxicities as well as more severe toxicities.
A second phase III trial, the (Avastin plus Docetaxel) AVADO trial, investigated the benefits of combining Avastin with a different chemotherapy, docetaxel, in over 700 previously untreated patients HER2-negative locally recurrent or metastatic breast cancer . In the primary analysis (data cut-off point: October 2007; median follow-up of 10.2 months), treatment with Avastin significantly increased progression-free survival compared to patients who received docetaxel chemotherapy alone . However, more recent analysis of the patient population evaluating overall survival (data cut off point: April 2009; median follow-up of 25 months) failed to define a statistically meaningful benefit .
A third phase III trial, the RIBBON-1 trial, evaluated chemotherapy (assigned at the discretion of a physician: either a taxane, an anthracycline or capecitabine) with or without Avastin for first-line treatment of stage IV HER2-negative locally recurrent or metastatic breast cancer . Avastin plus capecitabine compared with placebo plus capecitabine, and Avastin plus taxane or anthracycline versus placebo plus a taxane or anthracycline significantly improved progression-free survival but had no effect on overall survival.
In both the AVADO and RIBBON-1 trials, women receiving Avastin had an increased risk of death; 0.8% of women in AVADO and 1.2% of women in RIBBON-1 died from side effects thought to be related to Avastin .
A fourth phase III trial, the RIBBON-2 trial, which evaluated the efficacy and safety of Avastin in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer also significantly improved progression-free survival but failed to show statistically significant improvement of overall survival .
Thus, Avastin reproducibly increases progression-free survival but, on average, doesn’t keep women with metastatic breast cancer alive any longer than chemo alone.
Exceptions to the rule
The survival benefit identified in the four studies described above is an average, not an absolute. Avastin does increase overall survival in some patients. One of those patients is Christi Turnage, a registered nurse and breast-cancer survivor from Madison, Mississippi. Turnage started an online petition in the hopes of convincing the FDA to maintain the breast cancer indication for Avastin. Her son Josh wrote about the family’s fight in a plea to the FDA:
We did have a small bit of hope, though. Even though there’s not yet a cure for cancer, a new medicine — Avastin — had just been approved by the FDA, to be used in conjunction with chemotherapy. After just four treatments of medicine, all signs of cancer had left. My mom’s doctor couldn’t even find a trace of it.
In January 2009, my mom had her last chemotherapy treatment. Since then, she’s only been on Avastin. Twenty months later, she remains cancer free.
The problem with Avastin is that doctors don’t know which patients will respond favorably in terms of overall survival. In the majority of patients, Avastin increases progression-free survival but has no effect on overall survival.
When the FDA started discussing the possibility of withdrawing the indication for Avastin, critics of the agency accused them of rationing healthcare, claiming that it was Avastin’s high cost (as much as $100,000 a year), not its limited benefit, that the FDA cared about.
Although the issue clearly revolves around Avastin’s survival benefit, the FDA should be concerned about costs. Healthcare costs endanger U.S. financial stability. Simply ignoring the skyrocketing costs of healthcare and focusing exclusively on the treatment benefits, however small — in this case the average survival benefit is zero — will have a devastating effect on the U.S. economy.
Avastin should be placed in a restricted-access program so that patents already on the drug and benefiting from it can maintain access to it. Pharmacogenomics should be used to identify the best candidate patient population and a subsequent study should then be undertaken to determine biomarkers that have clinical utility in measuring the efficacy of Avastin in those patients. Several candidate biomarkers have already been described, including tumor and plasma VEGF, circulating E-selectin, ICAM 1 and VCAM1 .
We consider this a realistic and rational approach to provide effective, personalized therapy while simultaneously managing healthcare costs.
Indeed, patient advocacy organizations called for the use of personalized medicine stratetiges back in August to keep Avastin on the market for those who are most likely to benefit from the disease [8-9]:
We recognize the benefits of Avastin overall are modest for women with metastatic breast cancer. However, we do know that for some women, Avastin offers a greater benefit — but we do not yet know how to determine which patients will experience greater benefits. We have much more to learn about the drug and how individual patients respond to the drug, such as why some women receive greater benefit while others do not. Moving into the world of personalized medicine, cancer treatments will be more tailored to the characteristics of patients’ individual tumors. Yet, due to the current state of the science, we don’t always know which patients will benefit most before a drug is made commercially available. As with all medicines, we encourage a thoughtful discussion between a woman and her doctor that carefully considers the benefits and the risks. FDA approval is not a requirement for a doctor to prescribe a drug. However, the panel’s decision could limit the so-called “off-label” use of Avastin for metastatic breast cancer — or ovarian cancer, for which Avastin is currently prescribed off label — if third party payers refuse to cover the cost of treatment.
Miller et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76.
- D. Miles et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J. Clin. Oncol. 2008;26(155)(Suppl): LBA1011.
- Avastin improves survival in advanced breast cancer. Pharma Strategy Blog. 2008 Jun 2.
- Avastin for breast cancer shines in PFS but not overall survival. Pharma Times. 2009 Dec 4.
- Robert et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J. Clin. Oncol. 2009;27(155)(Suppl): 1005.
- FDA Advisory Committee Recommends against Bevacizumab for Metastatic Breast Cancer. NCI Cancer Bulletin. 2010 Jul 27.
Yang SX. Bevacizumab and breast cancer: current therapeutic progress and future perspectives. Expert Rev Anticancer Ther. 2009 Dec;9(12):1715-25.
- Statement on Avastin. Susan G. Komen for the Cure. 2010 Aug 17.
- Ovarian Cancer National Alliance and Susan G. Komen for the Cure Appeal to FDA and Key Lawmakers on Avastin Issue. Ovarian Cancer National Alliance. 2010 Aug 12.