Biology in the News Explained

The cost of chemotherapy drugs is completely unrelated to their effectiveness

A recent piece by Stephen Hall in New York Magazine seems to be the next welcome salvo in the pushback against the astronomically rising costs of drugs. The basic theme is that doctors are beginning to rebel against using newer cancer drugs that have shown no practical improvement over old ones, yet cost a lot more.

The system for developing new cancer treatments is broken. So far, there has been essentially no upper limit in what “the market” will bear in terms of the costs for drugs that are mostly fraudulently marketed as “life saving.”  The problem (arguably the same one for many economic problems in society at large) is one of incentives.

One of the most obvious of these is the Medicare Part D law which prohibits the federal government from negotiating drug prices with the drug producers. While there are often cases of legislation inadvertently creating perverse financial incentives, this is not one of them. Rather, it is an obvious result of a law that blatantly helps pharmaceutical companies at the expense of taxpayers, that those opposed to the law (mainly Democrats, as it was passed through a completely GOP-controlled government) decried at the time. Do we wonder why they don’t bother trying to come up with drugs that work, that aren’t prohibitively expensive?  Why would they when their largest buyer is required by law to give them whatever they ask?

Compounding on that, desperate people make desperate choices. Any amount, we think, is worth saving my life. Of course, there are several practical problems with this stance. First, almost no cancer drugs, ultimately, save one’s life; in fact, new drug approvals are often given on the basis of a median of weeks of life extension (even without regard to lower quality of life, due to side effects of the drug). Second, almost nobody is buying these few weeks with their own money; citizens who do not currently have major medical problems are paying for mine through their insurance premiums, and/or taxes. And unfortunately, the amount of money available for medical treatment is not infinite. One hundred thousand dollars spent on a drug for one person is not being spent on, say, preventative care for a whole lot of people. And because the sick demand our attention much more immediately than the healthy, it’s obvious what choice is generally made, and how the cycle continues.

But Leonard Saltz, at Memorial Sloan-Kettering (who have been the first to draw the line at offering a new expensive drug that provides no appreciable benefit), gets to the heart of the unsustainability of our chaotic, disorganized system of medical care:

“There is a number in people’s minds,” he says. “If you say to people, ‘I have a drug that extends life by one day at a billion dollars; shouldn’t we as a society pay for it?,’ I’m pretty confident most people would say no. If I say, ‘I have a drug that extends life by three years at a cost of $1.50,’ I’m pretty confident everybody would say, ‘Of course!’ Somewhere in there is a number, a tipping point, where we say, ‘No, we can’t.’ Right now, we’re unwilling as a society to explore where that point is. And I would argue that we have to. Wherever it may be, we have to find it.”

And it’s actually even much worse than this, because a median life extension of a couple months shown in a drug study does not mean that everyone who takes the drug will live for two more months. We’re not even getting what we think we’re paying for, because anyone reading a cancer drug study will see that what is actually happening is that a few people in the study get a pretty good response to the drug, a bunch of other people have temporarily stable disease, and the drug fails miserably off the bat for many, if not most, people. (Sometimes these studies are conducted without control groups, so the reasons for response or stability cannot be proven to be directly attributable to the drug.)

Unfortunately Hall doesn’t even get to this major point. Miserable side-effects (including death in some cases) aside, a huge amount of money for cancer drugs is being spent on people for whom there is no clinical benefit. One might expect that the FDA would require drug companies at least to attempt to determine the subset of patients who respond to the drug, but they do not. Occasionally, study authors do make an attempt, but only using crude, unindividualized data, despite the fact that we have a wealth of molecular tools at our disposal that could be used to genetically profile people’s tumors in order to run a multivariate analysis to give at least an idea of who the target population should be.

Although there are blood tests that can detect markers known to confer resistance to particular drugs or classes of drugs, chemosensitivity tests costing perhaps a few hundred dollars (which effectively would cost a lot less if a lot of labs offered them in competition with one another) are essentially unavailable to American patients.

It’s easy to see the financial incentives at play here. Why would a drug company reduce their potential market willingly? It’s much easier to believe that chemosensitivity tests don’t work (because they aren’t perfect) than to acknowledge they have a place in treatment, and have the industry (which includes clinical oncologists, who regularly make the declaration) lose potentially billions of dollars.

So, we are left with an incentive structure that rewards incremental “advances” in cancer treatment that each net doctors and pharmaceutical companies billions of dollars, at the expense of premium-payers and taxpayers. From Hall’s article:

Saltz says, “the fallback position was: Let’s see if the [old] drugs plus the new drug are better than the [old] drugs alone. And that’s how these drugs come to market … We start out with a new drug and get excited about it. We do big expensive studies with high hopes for it. And the drug winds up doing less than we hoped it would, but it gets on the market, and then it is both hyped and billed as if it did what we hoped it would do in the first place.”

The buzzword of “hope” is one of the most overused in the cancer industry, precisely for this reason. There is nothing wrong with hope based on a reasonable expectation that a treatment, however horrible to endure, will allow someone to ultimately live a significantly longer life. But “hope” in the cancer world is more often simply magical thinking along these lines — very expensive magical thinking. This leads to our current model of treatment development:

“Whereas we had hoped that small, incremental gains would be a springboard to something bigger and more productive, I fear those small, incremental gains have become a business model. Right now, it is safer for a pharmaceutical company to strategize for large-scale clinical trials that look for small, incremental gains that will get a drug to market, than to swing for the fences and try for the big advance.”

As I have touched on previously on Bioblog, when it comes to drugs that promote toxicity, even through mostly targeted action, there will not be any more big advances. For the sake of the millions of us suffering through these barbaric and expensive treatments, the oncological community must come to terms with the fact that a median life extension of two to four months is not actually a “breakthrough,” no matter how often they declare it to be.

Unfortunately the magical thinking is so pervasive that it has bled over to truly new treatments in immunotherapy that have a much better chance of meaningful life extension. From another recent article on research on a drug that ramps up the immune system in order to reduce tumor load (the way our body normally does it, and arguably the only way cancer is truly cured):

The findings, presented in October last year at a meeting of the American Society of Clinical Oncology, were striking. A significant proportion of patients responded, including 18 percent of 76 lung cancer patients who got the PD-1 drug and 10 percent of 49 who got PD-L1 drug. Dr. Pardoll…said that when she and her colleagues presented the data, “it was almost like a hush fell over the room: ‘Can this really be?’”

The cost for a course of PD-1 therapy? It’s $120,000. That’s right, for a drug that so far has helped 10-20% of those who took it (and carries the risk of sickness or death by autoimmune attack). It’s possible that drug companies will get away with higher pricing even more in the area of immunotherapy, because they can claim the treatment is “individualized,” and therefore more expensive (which is not actually true in the case of anti-PD-1).

And yet, this article ends, as many do, with what is supposed to be an inspiring anecdote:

In 2010, Mr. Gobin entered a clinical trial of an experimental drug that interferes with cell growth, but had no success.

Then his doctor at Johns Hopkins suggested a Phase 1 trial of an anti-PD-1 drug.

“Sure, I’ll do it,” Mr. Gobin recalled saying. “What do I have to lose?”

His tumors shrank significantly and have not grown, even though he stopped taking the drug eight months ago.

“Every day I have my feet on the grass is a good day,” Mr. Gobin said. “I was in the right place at the right time. I will always have cancer, but you know what, I can live with it.

“The Lord wanted me to be alive, and I am alive.”

Aside from the distasteful notion that God chooses the lucky few who respond to this treatment, it is a huge problem that we have let drug approval be guided by anecdote. As a corollary to Dr. Salz’s thought experiment on how much life extension is worth how much money, I offer a more accurate one: Is it worth a few hundred dollars to extend the lives of 100% of patients by five years? Most would say yes. Is it worth a trillion dollars (taken away from the rest of the country’s health care) to extend one person’s life perhaps by a year or two? Most would probably say no, probably many even when thinking about themselves. So where do we draw the line?

We haven’t drawn it because no one wants to, because it is hard and uncomfortable to do so. As Dr. Saltz suggests, it is partly due to this discomfort with discussing the value of a necessarily limited life that drug makers are raking in billions and millions of people are suffering and dying anyway. That’s the choice we make by refusing to have an adult conversation in which we collectively face the inevitability of death, rather than insisting that every incremental delay of the inevitable is a huge victory, worth any price.


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