Precision Medicine/Ambiguous Ethics?

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By Leonard Fleck, PhD

In his State of the Union Address President Obama announced that he wished to set aside $215 million for his “Precision Medicine” initiative. Given the cantankerous nature of Congress of late, this would strike many as needed political palliation. Who could be opposed to precision medicine? What member of Congress would stand up and defend “slipshod medicine” or “best guess medicine”? Fortunately, I am not running for any political office. I am not opposed to precision medicine, but there might be some ethical challenges that deserve serious consideration before the political lovefest begins.

There were two main parts to the President’s proposed initiative. One part would fund building a cohort of one million American volunteers who would agree both to have their entire genome sequenced and to provide their complete medical records to researchers. The other part would fund efforts to understand the genomes of cancer cells, the goal being to identify vulnerable features of those cells and then develop drugs that would target those vulnerable features. This yields the mantra most often invoked to describe precision medicine, namely, finding the right treatments, at the right dose, at the right time for the right person, every time. This is intended to contrast with much of contemporary medicine where many drugs have damaging and debilitating side effects, some worse than the disease they were intended to treat.

The cover story for Time Magazine (May 28, 2001) was headlined “There is New Ammunition in the War Against Cancer: These are the Bullets.” The “bullets” being referred to was the drug Gleevec (imatinib), which was used to treat chronic myeloid leukemia [CML]. The root cause of CML is a “fusion gene” known as ABL-BCR. Research had shown that if the activity of that gene could be halted the disease process could be contained as well. Imatinib was the magic bullet that did just that. Prior to imatinib, patients diagnosed with CML had about a 30% chance of surviving five years. After being treated with imatinib 60% of these patients could expect to be alive after five years. This is the beginning of “precision” medicine. No one should doubt that these were immediately recognized as astounding results.

In all the excitement no one seems to have paid much attention to the other 40% who failed to achieve five year survival. Why was imatinib not just as effective for them? The short answer was “resistance,” the ability of cancer to mutate around these drugs and begin again a deadly progression. The biological reason why cancers become resistant to these precision therapies is the genetic heterogeneity of most cancers. What this means, biologically, is that there might be one main driver for the proliferation of a tumor and numerous other potential drivers either of that tumor or of other tumors. This is what is described as either intratumor heterogeneity or inter-tumor heterogeneity.

Presently there are more than sixty cancer drugs that would be considered instances of precision medicine. That is, they are designed to target one or another of these drivers of proliferation. In general, the vast majority are only marginally effective, typically yielding extra weeks to extra months of progression-free survival at a cost of $100,000 or more for a course of treatment. The problem is that these drugs do “turn off” the main driver in some or most of the tumors that might define a cancer, thereby allowing other drivers to emerge in Darwinian fashion. This is the phenomenon known as resistance. The take home message is that most cancers are enormously more complex than researchers imagined twenty years ago.

The medical response proposed over the past three years is to follow the AIDs strategy, i.e., use multiple precision drugs, either in combination or sequentially, the goal being to make cancer for most people a managed chronic condition rather than a deadly condition. This might well be a medically appropriate goal but it is ethically problematic. About 600,000 Americans die of cancer annually; another 1.3 million are diagnosed with a cancer. If those 600,000 individuals can be given one extra year of life with the help of a $100,000 precision cancer drug, that would add $60 billion to the cost of health care in the US. If we were to use multiple drugs over five years to “manage” drug resistance, then the annual cost of these drugs for those five cumulative cohorts would be $300 billion.

Should we, as a just and caring society, be committed to achieving this goal? Is this something that we are morally obligated to do? If so, are we equally obligated to put just as much money and research effort into finding comparably effective life-prolonging interventions for all the other life-threatening medical problems individuals in our society face? Would anyone have a right to object to the additional taxes or insurance premiums that would be necessary to fight a “war on cancer” or a global war on all deadly diseases? And if we were unwilling to raise taxes or insurance premiums, then what current health care therapies would be defunded in order to underwrite precision medicine and the war on cancer?

Cancer is largely a disease of older individuals. So it seems inapt to talk about “premature deaths” in those cases. In order to control the social costs of cancer, should access to these precision drugs be limited to one course of precision therapy for those above age 75? Would that be an ethically defensible choice? This may sound ethically dangerous, but status quo options are even more ethically problematic. Individuals with very complete health insurance coverage would have very low-cost access to five years of precision medicine. But individuals with more modest (affordable) health insurance with high co-pays (30% or more for these Tier 4 drugs) would find it impossible to pay their share of the cost of these interventions, which means “ability to pay” would determine who had access to these drugs (though all Americans would have paid taxes for the basic research that made these drugs possible). Should that outcome be regarded as ethically acceptable because the implicit rationing is hidden from public view (no death panels making these choices)?

There are no easy answers to these questions. But there is no moral excuse for embracing precision medicine while ignoring the ethical ambiguity it generates.

References:

Fleck smallLeonard Fleck, PhD, is a Professor in the Center for Ethics and Humanities in the Life Sciences and the Department of Philosophy at Michigan State University.

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