Avastin: Making sense of the controversial breast cancer treatment drug
In a series of unanimous votes, an advisory committee to the Food and Drug Administration endorsed the agency’s proposal to revoke the approval of Avastin for use in the treatment of advanced breast cancer. The appeal hearings about the decision were emotional, even hostile, as breast cancer patients pleaded with the panel to rethink their position.
At the same time, European regulators announced that they were expanding Avastin's breast-cancer indication to include its use in conjunction with other chemotherapy drugs. The European position has now added fuel to an already inflamed controversy, furthering confusion and outrage to the debate. The European Medicines Agency’s announcement, coming within 24 hours of the final FDA vote, has added a surreal quality to the controversy. As consumers of health care, we are left to wonder which experts to trust, and just what political forces motivate these decisions.
The FDA committee voted that the drug was neither safe nor effective, and rejected a proposal by the drug’s manufacturer, Genentech, to keep the drug approved until the company conducts another rigorous clinical trial.
About a dozen women many of whom said the drug was saving their lives, and some cancer support group advocates, pleaded with the FDA and the advisory committee to keep the drug available. At the same time, the FDA panel insisted that no matter how they looked at the existing statistics on the effectiveness of Avastin, they could not come up with a sufficient reason to keep it approved.
“The agency has to look at protecting a larger number of patients,” said one committee member, Dr. Ralph Freedman, a gynecologic oncologist at the M. D. Anderson Cancer Center in Houston. “Sometimes they have to make a decision that doesn’t favor individual patients, but it’s on the basis of the whole.”
Avastin received an accelerated approval for breast cancer treatment in 2008 under a new program that allows drugs for serious diseases to reach the market quickly, subject to further study. In December of last year, the FDA said that later studies on Avastin’s effectiveness did not confirm the initial findings that it could be an effective treatment for advanced metastatic breast cancer.
Breast cancer patients who testified at this week’s hearings expressed outrage that their cases were treated as statistical outlier anomalies unworthy of being taken into consideration. They also pointed out the salient fact that none of the panelists were experts in metastatic breast cancer.
The decision has yet to be finally approved by FDA Commissioner Margaret Hamburg, who does not necessarily have to follow the panel’s recommendation. Genentech might also challenge the decision in court. In either case, Avastin is not going to disappear off the market. It is still used for the treatment of other metastatic cancers, and may likely be used off-label for the treatment of metastatic breast cancer. Off-label use for drugs is fairly common practice, though Avastin’s price tag - $88,000 a year – might prove a daunting case for insurance reimbursement, and that is probably the biggest sticking point in the whole controversy. Insurers might be far less likely to reimburse a drug for off-label use when its costs are as steep as Avastin’s.
Medicare is supposed to pay for off-label uses of cancer drugs listed in references called compendia. One such compendium, published by the National Comprehensive Cancer Network, reaffirmed support for Avastin last year. However, an explicit rejection by the FDA might prompt a re-evaluation of the compendia.
The debate rests on three clinical drug trials of Avastin, one of which showed promising results, while the other two showed none. In the first trial, Avastin, when combined with the chemotherapy drug paclitaxel, appeared to delay the median time before tumors got worse by 5.5 months compared with paclitaxel alone. In two subsequent studies, Avastin delayed tumor progression by only 1 to 3 months. Importantly, none of the studies, including the original one, showed Avastin prolonged women’s lives or improved the quality of their lives.
But drug trials address statistical probabilities, not the realities of outliers and exceptions to the rule. Exceptions to the rule always exist, and the dozen women at this week’s hearing were those very exceptions. The crucial question they are asking us to consider is, should their life-saving interventions be cut short because they do not fit the statistical curve? Surely exceptions should be made for exceptional cases. An official ruling by the FDA might make that very difficult.
Sinister political forces do not appear to be behind the FDA panel’s decision. After all, it was the pharmaceutical giant that lost this particular battle, and it surely had (and will continue to have) a fierce legal arsenal to protect its stance. But what are we to make of it in light of the European approval of Avastin for the very same condition?
Europeans have been conducting their own clinical trials of Avastin, in combination with a chemotherapy drug called capecitabine, which appear to directly contradict the findings cited by the FDA. Some of the findings included:
• A 45 percent increase in the likelihood of women being alive without disease progression compared to those who received capecitabine alone
• A median PFS (progression-free survival) of 8.6 months compared to 5.7 months in those women that received capecitabine alone.
• 35.4% of women experienced a major shrinkage of their tumor compared to 23.6% of those receiving capecitabine alone.
The lesson here is that clinical trials are themselves flawed – there simply is no such thing as a perfect clinical trial. Comparing the contradictory results of the different trials only shows that we need more time – certainly more than two years – to see Avastin prove its mettle.