The FDA’s recommendation to rescind Avastin’s metastatic breast cancer indication provoked a mix of commentary, commendations, and outcry from across the spectrum of stakeholders with an interest in the decision – and in what the decision might mean for the future: the future of cancer therapy approvals, evidence-based medicine, coverage for off-label use, drug pricing, and healthcare rationing … among other things.
This debate lies at the center of a tangled web of science, psychology, politics, economics, and ethics. Science and psychology, in particular, collide here in a way that reminds us of the challenge of selling the public on evidence-based medicine.
We are built by evolution to see cause-and-effect. The subset of women with metastatic breast cancer who have done well on Avastin almost cannot help but believe that they have done well because of Avastin. And it is no easy thing to overcome this built-in visceral conviction with the dry logic of rationality or the weight of evidence from patients treated in groups rather than as individuals.
When we’re able to be objective, we know that cumulative failed trials of a drug – particularly one that comes with noteworthy risks of serious adverse events (as Avastin does) – nullify the original justification for drug approval.
But the very success of Genentech’s other breast cancer drug – Herceptin – is a nagging source of doubt, even for those of us inclined to accept what today’s best science tells us about Avastin’s breast cancer value. Herceptin confers clinical benefit only for the minority of breast cancer patients whose tumors overexpress the Her2-neu protein. We have laboratory markers for Her2-neu that allow us to pick out the subset of patients who will benefit from the drug and to forego the drug in the rest.
It is altogether possible – maybe even probable – that today’s best science just isn’t good enough yet to have identified a causal link between Avastin and the positive outcomes in the subset of patients who have done well on the drug. In fact, suggestive data already exist for the potential value of markers such as tumor and plasma VEGF, circulating E-selectin, ICAM-1, and VCAM-1, and Genentech tried to argue for confining Avastin use to selected patient genotypes. There are even provisional data suggesting that some genotypes (VEGF-634 CC and VEGF-1498 TT) are associated with less grade 3-4 hypertension – a finding that could change the risk-benefit calculation for the drug. But no marker as promising as Her2-neu has revealed itself for Avastin, and no prospective trials establishing the clinical utility of any biomarker have been completed.
Where does all this leave patients? For now, Medicare has said it will continue to pay for Avastin despite the FDA’s recommendation that the metastatic breast cancer approval be withdrawn. In fact, a CMS spokesman said that, “The FDA decision, when it comes, does not affect CMS.”
Those who defend the FDA’s unanimous vote to rescind Avastin’s breast cancer approval do so by saying that it reflects today’s best science. Perhaps CMS is saying that the best science just isn’t good enough, but we could just as legitimately conclude that CMS is saying that today’s best science does not affect CMS. And if that’s what they’re saying, it’s a near-victory for irrationality and optimism over science. Coverage for breast cancer is de facto endorsement. Shouldn’t we challenge that endorsement if, by standards governing every other drug, Avastin doesn't warrant confidence?
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