Last month, an FDA advisory board recommended withdrawing government approval of Avastin as a treatment for advanced breast cancer. The decision betrays a bias that puts costs above treatment, and unless the FDA leadership overrules its own experts, the 40,000 women killed by breast cancer each year will be denied an important clinical option.
Avastin is a biologic that works by choking off the flow of blood to tumors and is approved for lung, kidney, brain and colon cancers. But it is loathed by many in the medical and political establishments because it also very expensive. Roche’s Genentech unit charges as much as $88,000 annually for an Avastin breast cancer regimen, reflecting the costs of development and production.
The FDA allowed the use of Avastin for metastatic breast cancer in 2008, under the “accelerated approval” program for drugs that show promising evidence against life-threatening diseases. Avastin’s dispensation came in spite of a negative 5-4 ruling in 2007 by the board known as the Oncology Drug Advisory Committee, or ODAC.
ODAC decided that Avastin did not meet what the FDA considers its acid test: Patients did not live longer—that is, the overall survival rate did not improve in a statistically significant way. Yet a clinical trial showed a 52% median improvement in “progression-free survival,” which measures the time women live without their disease spreading or worsening. In practice, this means delaying the growth of tumors by about 11 months in combination with chemotherapy—five and a half months longer than chemo alone.
Metastatic breast cancers remain incurable, so the main goal is to improve quality of life: Oncologists try to control the spread of cancer and delay the onset of symptoms. Having more than one treatment choice is itself a real benefit for patients, minimizing psychological suffering and offering hope.
ODAC met again in July to consider Genentech’s request for conversion from accelerated to full approval, with new data at its disposal. Astonishingly, it ruled again, this time 12-1, that Avastin’s progression-free survival advantages are not clinically meaningful.
True, the follow-up outcomes were not as robust as the original verdict. One trial showed a 36% improvement, another 31%. Critics claim these effects are worthless because they translate into only one to three extra months before tumors worsen. But variation is to be expected over several studies, which in this case both the FDA and ODAC agreed met their gold standards for placebo-controlled clinical trials.
Remember, too, that these are only averages over a narrow population, while individual patients respond in dramatically different ways. That includes prolonging survival, which Avastin does in some situations. The median overall survival benefit for one subgroup of 496 patients between the ages of 40 and 64 was an additional 5.7 months of life. Some individuals gain years. At any rate, even the 31% reduction in the risk of disease progression or death is better than the status quo.
Such quantifiable progress, moreover, was the “endpoint” that Avastin had been required to hit. In February 2009, the FDA confirmed that the drug would be approved if it showed “demonstrated improvement in progression-free survival and evidence that survival is not impaired,” according to the agency’s minutes.
The FDA later unilaterally redefined its regulatory expectations, devising a pretext to undermine Avastin. The terms of ODAC debate are set by instructions from FDA staff reviewers, and in round two they suddenly emphasized topics that had been resolved in round one, such as the lack of overall survival benefits and safety issues such as toxic side effects.
The latter can include severe bleeding and other life-threatening complications, though they are manageable. Some 812,000 patients world-wide have been treated with Avastin, 90,000 with metastatic breast cancer, and its safety characteristics are well understood. As for survival, Avastin hasn’t been shown to extend life on average—but it doesn’t impair it on average either, even as patients are enduring the savagery of traditional chemotherapy.
ODAC chairman Wyndham Wilson, a National Cancer Institute lymphoma specialist, conceded that Avastin’s side effects only affect “small numbers,” but “if you’re the one, that’s not what you want to be exposed to.” But what if you’re “the one” for whom Avastin offers massive breast cancer relief, or a reprieve of a few months at the end of life?
Dr. Wilson added that “I think the good housekeeping seal of approval is important and I think that it needs to reflect what the data shows.” In other words, the FDA’s regulatory afflatus is more important than options for actual patients with a deadly cancer who are informed of the risks. (As usual, the FDA didn’t return our calls for comment.)
While ODAC is ostensibly independent, it is in practice a creature of the FDA and the FDA’s political masters in Congress. The agency appoints the rotating ODAC members, which is like a prosecutor choosing his jury. The agency’s oncology leaders—led by cancer drugs chief Richard Pazdur—routinely stack the panel with people who share their dislike for industry and accelerated approval. In recent years the FDA has also tightened conflict-of-interest rules, which means that ODAC’s “experts” often have no specific expertise treating the diseases that the drugs they are adjudicating are meant to treat.
Few of the Avastin panelists had any first-hand clinical experience with metastatic breast cancer. Six of the 13 members sat on the ODAC panel that judged Avastin in 2007 and five of them were invited back by the FDA on an ad hoc basis as “temporary members.” They ought to have recused themselves if only to preserve the appearance of impartiality.
One of them was Natalie Compagni Portis, a member of the original panel and amazingly enough its “patient representative.” She said, “Hope is very important. But to offer hope that isn’t substantiated I don’t think is responsible.” Jean Grem of the University of Nebraska explained her anti-Avastin vote by observing, “We aren’t supposed to talk about cost, but that’s another issue.”
So here we have government-anointed medical patriarchs substituting their own subjective view of Avastin’s risks and costs for the value that doctors and patients recognize. If Avastin is rescinded, thousands of dying women will lose more than proverbial false hope in the time they have left. They will lose a genuinely useful medicine.
Avastin’s opponents absolve themselves of any moral qualms by claiming women could still be treated “off label.” The ODAC members repeatedly brought this up during the hearing. But private insurers and Medicare are reluctant to cover treatments that aren’t recommended by the FDA.
The Avastin mugging is really an attempt to undermine regulatory modernization like accelerated approval that offends the FDA’s institutional culture of control and delay. It is also meant to discourage innovations like Avastin that the political and medical left has decided are too costly, with damaging implications for the next generation of cancer drugs.
Investigations at the frontiers of genomic science have only begun, and the learning curve for how subsets of patients respond to biologics, and how to target them, is steep. Yet the world’s oncologists agree that the future of their science lies in patient-specific, biologic treatments. Cancer survival rates have improved gradually over the last several decades, thanks in part to improvements at the margin like Avastin.