The skeptic: What precision medicine revolution?
The benefits of genomic drugs are exaggerated, hurting patients and the practice of medicine, says one high-profile oncologist.
Vinay Prasad is relatively young (35) and still climbing the academic ladder (he’s an associate professor of medicine at Oregon Health & Sciences University in Portland), but he has already established an outsize reputation as a “professional scold” for his sharp critiques of contemporary biomedical research, including personalized medicine. In commentaries in high-profile medical and scientific journals, and in a Twitter account with some 25,000 followers, Prasad has questioned the evidence (or lack thereof) to support the use of precision oncology, the practice of selecting drugs for patients on the basis of specific mutations in their tumors. He has also criticized the inflated cost of cancer drugs and the financial conflicts of interests bedeviling contemporary research.
Prasad brings several unique perspectives to the role of medical scold. Born in Euclid, Ohio, outside Cleveland, to an immigrant couple from India, he developed an interest in philosophy in college before attending medical school at the University of Chicago. As a practicing oncologist, the prolific Prasad has generated a boatload of peer-reviewed papers, gathering evidence to suggest, among other things, that genomic-based evidence hasn’t made much of an impact on cancer patients. As a sometimes prickly online persona, he has been faulted for unleashing expletive-laden putdowns but has also attracted a robust audience for what he calls “tweetorials,” which dissect the design of high-profile studies and the data they generate. In the following conversation with veteran medical writer Stephen S. Hall, he takes aim at “precision oncology,” the gaps in direct-to-consumer genetic testing, and what it really costs to bring a new drug to market.
Proponents have been promising a revolution in personalized medicine for decades. What’s the reality?
I would say, and I think many people will agree, that the promises that were made around the time of the Human Genome Project have largely not materialized, and that the impact of personalized medicine has probably been exaggerated.
What’s the danger of exaggerating the promises?
I think we have a schizophrenia in science and medicine. On the one hand, people who are good scientists understand that science is difficult. You should not be, nor will you be, having breakthroughs all the time. Breakthroughs are rare. Science is hard. It takes years of slogging to understand very fundamental pathways.
On the other hand, we often are tempted to—and I see experts continue to—make grandiose promises, and have a lofty, unrealistic vision for what might be achieved in the next few years.
That harms the public understanding of science, because the public comes to believe that unless you guys and gals are producing breakthroughs all the time, we shouldn’t be funding this. That’s wrong, because science needs more funding—needs a lot more funding than what we’re currently investing.
Does it hurt the patient?
I would say inflated rhetoric about the value of medical practices, technologies, or science harms patients because it distorts their understanding of what a therapy or intervention might do. And by distorting the understanding, it robs them of autonomy. I’ll give you just one example.
Sometimes cancer patients are on medications that add real side effects to their life, but they believe that there’s going to be some survival benefit by taking this medicine. Every person is making kind of a daily decision: Do I stick with this medicine or not? Are the side effects worth it to me or not? And if that decision is made in a very impartial way, with a good understanding of what the drug does, that’s the right way. But if that decision is made under the cloud of hype, when it’s surrounded and marinated in hype and misinformation, then I think what we’re really doing is that we’re preventing the person from making the decision compatible with their wishes. We’re kind of taking away that choice. And I do fear that that happens quite often.
You recently published a study indicating that most cancer patients don’t benefit from personalized genomic medicine, even though it’s been in practice since at least 2006. Why do you think that’s the case?
Some people have said that study is pessimistic. It’s neither pessimistic nor optimistic; it is simply the most realistic estimate of how many people have benefited from genome-driven therapies. There clearly are some situations in cancer where drugging a single cancer-causing gene is important, and that should not be taken away. Those clearly do exist.
The problem is that they simply don’t exist for the majority of patients who will be diagnosed with metastatic cancer. The purpose of our paper was to document what that number is, and what has been the change over time. I’ve heard the rhetoric that we’re reaching exponential growth, or that [precision oncology] is taking off, or there’s an inflection point. We simply don’t see that evidence if you look objectively at the data.
Does that mean you’re reluctant to use them in your own practice?
Of course I use genome therapies. I love [them]. Where they work, they work well. In fact, I would increase the funding to research them. But at the same time, I think we should be realistic about their prospects. We’re also doing that same kind of analysis right now for immunotherapy drugs and cytotoxic drugs and different kinds of drugs. Can we more accurately compare what has been the impact of these different types of therapies?
In a recent article, you suggested that if adopted prematurely, the use of precision medicine might actually increase the risk of inappropriate medical care. How so?
Every day there are new potential treatments or therapies or strategies to treat any disease, and they all have some degree of bio-plausibility. When it comes to a new cancer drug, bio-plausibility is just not enough. You should also test it and prove that it does what you think it does. Precision medicine should be held to the same standard.
One of the differences is that precision medicine is very, very seductive. Some of its bio-plausibility is just such a compelling story that I think we do see this temptation by proponents that it shouldn’t be assessed in the same way. It’s so plausible, it should just be adopted—that kind of attitude. That kind of attitude might paradoxically lead us to adopt potentially more things that ultimately turn out not to do what you think they should do.
Do you think direct-to-consumer marketing by companies like 23andMe has made it seem as though personalized medicine has arrived already?
Yes, I think the constant rhetoric that this is wonderful has shifted the public perception. In terms of the direct-to-consumer advertising, we actually have a paper on the BRCA breast cancer gene test that appeared in [the Journal of the American Medical Association] about a month or two ago. It points out that there are some limitations to that direct-to-consumer BRCA testing. The test is actually only for three mutations that are very common in the Ashkenazi Jewish population, but not perhaps the most common BRCA mutations among all people with deleterious mutations. And thus there are some unintended consequences. A woman with a family history who may be worried will send off that test, get a negative result, and feel reassured. But that person may have a deleterious BRCA mutation. It may actually be counterproductive.
If genomic testing and these other aspects of personalized medicine are not currently predictive of outcomes for individual patients, are the drug companies and medical institutions taking advantage of consumers by pushing these methods?
It’s a big category, and there are some things that are very well validated. But I think there are some things that are not. And the consumer doesn’t always know which ones are which, and that’s the challenge. Even some of the people in the field apparently seem to forget which ones are which, and that’s what I try to remind them of.
When you remind them, it sounds like you get pretty strong pushback.
I appreciate pushback when it’s about the technical merits of any of these arguments. Where I think pushback is counterproductive is when pushback becomes personal or when pushback is about the intention.
There are a number of people who have voiced concern that one or more precision therapies don’t have the data. And sometimes I feel as if the argument devolves into the people who want that therapy saying, “Well, we want what’s best for patients. And you people who are saying that we don’t have data, you apparently don’t want what’s best for patients.” I think we have to recognize we all want what’s best for patients. This is an argument about the evidence. And I get personally frustrated when I see people try to pervert the argument in that way.
You’ve also criticized the high cost of drugs, and you recently argued that industry estimates of the cost of bringing a new drug to market are wildly exaggerated. What does it really cost?
I think that the cleanest estimate that I’ve seen—and I’m a little bit personally biased—is the estimate that Sham Mailankody and I put out in JAMA Internal Medicine, where we estimate that it costs something like $800 million in R&D to bring a cancer drug to market. The industry estimate is $2.6 billion. There’s a big difference there. But at the end of the day, this is one of those few things in life where you don’t have to settle for estimates. Since the industry repeatedly uses the cost of R&D as a justification for the high price—and unsustainable price—of drugs, I think it’s probably fair game for governments to ask them to show the data. Let’s just put all the data on the table and let’s see what it really costs.
One of the other things you’ve suggested is that the expert panels that advise the FDA have financial conflicts of interest. Is that compromising the quality of medicines that consumers are getting?
I just want to clarify my view here, which is that I wholeheartedly support collaboration between academic investigators and for-profit companies. The additional complexity and challenge is when you have payments made to physicians personally. I think those payments—and they’ve been shown to—do affect our perception of products. If you’re receiving a lot of money from a manufacturer, you may not view their product as impartially as you would if you were not receiving that money. That’s the concern. I think we should try to curb the financial conflicts of for-profit companies in the healthcare space.
There are some legitimate questions here about the role of financial conflicts in this space. Does it distort the impartiality around adjudicating medical practices? I fear it does.
Given the implications of the kind of critiques that you have been publishing pretty prolifically, why aren’t more people saying the same thing?
I ask myself that all the time. These questions feel very obvious to me. There are a lot of people who do care. A lot of them are general internal-medicine folks. I think we see it a little less in the specialties. And I think we see it much more in the younger crop of physicians than the older crop, in the sense that people who have done this, practiced for many years in this environment and who have found their niche in the environment, they’re comfortable where they are, and they don’t really feel the urge to comment about these more problematic areas. But people who are younger, and approach this field with fresh eyes, feel as if these things are problematic.
You don’t always sound like a scold.
I’m very optimistic about science, that we will improve outcomes. I just think that we would benefit from a lot more empiricism and impartiality in the process. That’s what I feel is missing—empiricism, impartiality, and more modest rhetoric. I think those three things would go like 90% of the way.
Is it true, as reported by The Cancer Letter, that you’ve closed your Twitter account?
No, it’s not true at all! I’m on Twitter, @VPplenarysesh. I believe that there are a number of inaccuracies in the Cancer Letter stories about me. I’ll save that for another day.
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