Rethinking Research

Harlan Krumholz: Welcome to Health & Veritas, I’m Harlan Krumholz.

Howard Forman: And I’m Howie Forman. We are physicians and professors at Yale University, who are trying to get closer to the truth about health and healthcare. There is a lot going on in the world, but healthcare doesn’t stand still even as we bear witness to unthinkable violence. We don’t have a guest today, but Harlan, you and I have a lot to catch up on in the area of healthcare and COVID. What is top of mind for you?

Harlan Krumholz: Yeah, I wanted to start again with COVID. There’s an interesting thing brewing that probably people should take notice of. There was a nice tutorial that I saw this week from a guy by name of Ulrich Elling, who’s a scientist in Germany. Hat tip to [Eric] Topol, who’s usually my source for picking up on tweets that I don’t see right away. Elling was talking about the next variant. Let me just say, I think we’ve been in a sweet spot since last February. We’ve been in a period where yes, there’s been some spread of BA.4 and BA.5, variants have been coming through the pike. But people have gotten sick, but largely it seems like in highly vaccinated areas the excess mortality, the increased number of deaths over what might be expected, has not commensurately risen like it has in prior waves.

Somehow this pandemic, to the extent that it will ever be, has been under control. We haven’t been overrun in the hospitals. People have gotten sick. People stayed home from work. It’s not that it hasn’t been inconvenient. And it’s not that people haven’t died, especially those who are unvaccinated, still at risk, but in highly vaccinated areas, like I said, at least in the last several months, it seems like we’ve been in a situation where there haven’t been a lot of excess deaths. That’s led the nation, I believe, to become quite complacent about this. As you know and we’ve discussed previously, Howie, Congress has yet to really endorse, with a large amount of support, the strategies that we need to prepare us for the future. As you look around the country, most people, I believe, have the sense that we’ve gotten back to normal, that things aren’t quite what they were.

I think I’m here to say that if you look down the pike, it’s just going to be, I think, a world where this is going to circulate for whoever knows how long, and we’re going to be in a position where it depends on the variant as to what’s going to happen in society, that is, with regard to the harm. And it’ll be up to us to try to find strategies that will mitigate these variants that come out that are tougher and harder.

All this is prelude to say that there’s one coming down the pike that is concerning. One of the issues about these variants... people may hear about this thing called NTD, the N-terminal Domain. It describes a place within the spike protein. Now, everybody almost knows now that there’s a spike protein that is what most of the antibodies are directed against. The vaccines were helping us to produce antibodies to that spike protein. Everyone has seen this ball with spikes coming out from it. It’s those spikes that have been the targets. Within that spike, there’s a region that has been critically important for those antibodies to attack that have helped us to protect ourselves against the coronavirus. What’s coming down the pike is a thing called BA.2.75. That may be a new lineage to worry about because unlike a lot of things we’ve seen before, there are a lot of mutations in that area that is so important, so critical to our protection.

It looks like it’s an evolutionary jump from the BA.2. It’s been seen mostly in India at this point, but it’s spreading really rapidly. We have yet to really see it in the United States. What people are concerned about is that it’s on its way. A couple of the things I think to note about it is that it really is that these mutations within this variant are right around those binding sites for the antibodies, right around those areas that are providing the most protection. Some people are saying that this variant is even more infectious than anything we’ve even seen before. When people try to provide a benchmark for infectivity, they talk about measles. Measles is one of the most infectious viruses that we have. Some people are suggesting... And I saw [Peter] Hotez, who’s a Yale grad, was actually in my class, a terrific scientist and has been a really courageous spokesperson on behalf of very sensible public health measures within the pandemic, has also said this, which is that the relative transmission could be rivaling what we see in measles. And that’s getting everybody really concerned, that is, those who are in that sphere.

Now look, everything, it depends on what happens as things spread. And all these are speculation at this point. It’s just, again, doubling down on this notion that we’re not through this and we’ve got to figure out what our steady state’s going to look like that allows us to be agile so that when we’re threatened by something that is evolving towards something more dangerous and more transmissible, that we’re able to quickly ratchet down the behaviors that may help spread this. The question is, can we find a balance where we can keep our economy going, where we can help people to live their lives, but take the most effective steps that we can in order to at least slow the spread a bit so that we’re not overwhelmed with some variant that, again, rivals measles? That is on my mind. I thought this was a concerning set of circumstances. I don’t know if you’ve heard about it or if you have any thoughts on it.

Howard Forman: Look, I continue to be worried about the fact that we are relying a lot on previous immunity from both infection and vaccination, and that we haven’t really been challenged with something that evades that immunity completely or nearly. The one thing I will say that comforts me at the moment, obviously with Omicron variants, is that I’m still seeing a lot of people coming into the ER with COVID. I’m seeing almost no radiographic COVID, as I did a few months ago, in January, February. That’s a favorable thing to me.

We’ve had very high prevalence of positive cases in Connecticut. We’re seeing very little actual morbidity relative to what we have in the past. That could change a lot in September, October. As you point out, it could become both a new variant that evades our current immunity, it could be more infectious, it could have different symptoms, which we’ve seen over time. To the point that you’ve been making consistently, we still have no answers about whether the second infection or the third infection has meaningful risk of long COVID relative to first infections. We don’t have answers to that yet.

Harlan Krumholz: There was an article that came out that said the more times you’re infected, the higher your risk of long-term problems. The issue, I think, is that what you’re describing is that period that I mentioned in which we have not seen excess deaths, but the question is, what’s the next variant? You’re projecting to the fall, that is, believing that this has a seasonality to it. Maybe there’s a hiatus still in the summer, hard to know. And then of course, there’s this looming thing about long COVID that sits around all the time. I can’t tell you the number of people that I interact with who are suffering terribly with a life that has been unraveled since infection with COVID.

In addition, I raised this before, I think we should have a whole episode talking about vaccine injury. There’s people who believe that they’ve been injured from the vaccine who have a very compelling story about it, who were previously very healthy. And we’re turning away from those people because we’re afraid to talk about potential adverse consequences of the vaccine, because it’s in the milieu of everybody trying to avoid this anti-vax mentality. Both things can be true. The vaccine can be a large net positive, and there still can be some small number of people who are devastatingly harmed by it. We’ve really got to approach this scientifically, not be afraid of it politically, but to be concerned about what people are experiencing and lean forward into it.

I think all these areas are... there’s the acute manifestations, there’s some variants around the block, and then there are the consequences of what we’re doing, whether it be with regard to interventions or whether it’s regard to the virus itself. This remains a very important area. I’ll give you one other caveat about this that concerns me. I am not seeing scientists tack toward this area. There’s a small number of scientists who are deeply involved in many of these issues, especially long-term consequences.

First of all, there’s no existing cadre of scientists who’ve been focused on this area. And the second one, it’s a very high-risk thing to do for your career, not knowing how long is this going to last, what are the issues, what’s funding going to be like? Are people going to take these patients seriously, given that we have yet to have objective reflections of their biology that suggests to monitor them and so forth? What field does it fall in? It’s not really infectious disease. It’s sort of immunology, rheumatology, some of it’s neurology, some of it’s cardiology. So these are also things that concern me. Who are the scientists that are really going to devote their lives to this? It’s not clear.

Howard Forman: And one limitation we have is we have a very, very scattered healthcare system in this country, if you want to call it a healthcare system at all. But it’s surprising to me that even the UK and Israel, which have more nationalized healthcare delivery, have not been able to generate that specific type of data that we would like to have, that would answer some of these questions. We’re just not seeing it. And I think you’re right, a lot of public health people and modelers have invested their efforts in COVID, not as many clinical trialists and people who are invested in large ongoing cohort studies in the way that Amy Justice, our prior guest, has been involved in.

Harlan Krumholz: I don’t know. The take-home for me is that I think as a society, we need to take all these things really seriously. We need to continue to invest in new knowledge about it. I think for the public, we need to help people know that there are sensible measures people can take that don’t mean that they need to isolate themselves completely, or that they have to withdraw from life or that are going to wreck the economy. But that there are ways to operate that can still be sensible. And we need to be monitoring the environment when there are very few cases of COVID and COVID isn’t causing much problem. That’s one scenario that requires a very different response than one where hospitals begin to be overrun, people are getting sick, and the illness is highly threatening to their lives.

Howard Forman: Let me ask you this, Harlan. I saw you tweeted about this, and this is a longstanding question of do various fish oil tablets over the counter, as well as some types of prescriptions, do they work or not? There’s this fascinating recent publication that you are very well versed in. I’d love to hear your take on that. And particularly even explaining to us why this is such a big concern after decades of people making such recommendations.

Harlan Krumholz: Let’s pivot off COVID for a minute and try to see if we can go in another direction. In cardiology, we’re always looking to see what can we do next that might be able to lower people’s risk. And we’re concerned that even people who have very good control of their risk factors, many of those people still suffer from heart disease. And so we call that residual risk. People still have risk despite the fact that we’ve done a good job controlling blood pressure and their LDL cholesterol, that “bad cholesterol,” and so forth. We’re always on the hunt for what can we do better? What can we do next? And one of the things that has reared its head from time to time is this question of, what about fish oil?

Almost everyone’s heard about the idea that fish oil can do this or that. How does it help you? Lots of people... American Heart Association suggests that people should be eating fish, especially oily fish that has what’s thought to be healthy oils. These are fatty acids that we think by some way or another helps to improve heart health. Turns out, over the years, it’s been a highly contentious area without clear resolution. There’ve been some times where studies have suggested maybe it’s helpful and then almost soon after another study suggests it’s not helpful. And then there are many different kinds of these fish oils. And so one company got approval to sell fish oil for its effect on lowering triglycerides. So for people who’ve got elevated triglycerides, sometimes they can be at elevated risk.

One of the nuances of the way that the FDA works is, in approving something for lowering triglycerides, people don’t actually have to show that they improve health outcomes. And this has been a problem, this disconnect, because you can actually make someone’s labs look better and actually end up causing higher risk even than you might have thought. And there’s plenty of examples of that, where, for example, drugs that... many drugs, by the way, that lowered triglycerides. Niacin, for example. Gemfibrozil is another. Fibrates, that were used for a long time, they were advertised everywhere, on billboards at all of our national meetings because they lowered triglycerides. And it took a while before the studies came out and said, “Hey, by the way, your labs look better, but people didn’t have better outcomes.”

Howard Forman: In some cases we’ve seen worse outcomes in situations like that. With diabetes drugs, where we saw better glycemic control but worse cardiovascular risk.

Harlan Krumholz: So I’ve been beating this drum for a long time, is that we really need to be looking at outcomes. What actually happens to patients? There was another study that Pfizer ran, on a drug they were just about to start selling and had decided to do an outcomes trial on. I don’t think they would’ve been mandated to do so. They could’ve just sold it because it made the good cholesterol look so much better. And it turned out that people died at greater rates who got that drug inexplicably. Nobody could even now tell us why that happened. But we really needed to do the experiment to find out. So this drug, icosapent ethyl, is a pharmaceutical-grade fish oil that was tested in a randomized trial called REDUCE-IT. The trial, which was published in The New England Journal of Medicine in January of 2019, had a blockbuster finding, a jaw-dropping result.

They randomized about 8,000 people, and it had about a 25% reduction in risk. Twenty-five percent reduction risk. We almost have never seen—that was better than statins. I think a lot of us were sitting there going like, “Gosh, that’s unexpected.” We were wondering whether it would have any benefit, but that big a fact, 25% reduction for essentially a dietary supplement. Man, this is pharmaceutical-grade. It’s made a little bit differently, but it’s an oil. And taking an oil. So a lot of people were really celebrating this. It got into the guidelines, been promoted. People were really happy about this. By the way, this study went for about five years. Looked like it was a very well-conducted study. Like I said, in The New England Journal of Medicine, top journal.

In the course of getting the approval from the FDA, it came out that in the placebo group, they had used mineral oil. And in that mineral oil group, some of the biomarkers, some of the things that we measure risk, like LDL cholesterol, actually went up in the mineral oil group. And C-reactive protein, a marker of inflammation, went up in the mineral oil group and didn’t really change in the icosapent ethyl group. Vascepa is the name that it was being sold under. And people started raising the question: “Maybe this trial was using a non-neutral comparator. Maybe the placebo wasn’t neutral at all. It was actually worsening outcomes. Maybe there’s something about the mineral oil they were using.” And they picked the mineral oil because they wanted something of the same consistency as the oil, felt like an oil, but—

Howard Forman: If you wanted to keep it double-blind, you want to give somebody something that’s going to seem similar. It made sense.

Harlan Krumholz: And there was another trial of a different type of fish oil, but kind of similar, that used corn oil, which didn’t find this effect and found no benefit of the fish oil, essentially. The kind of oil we’re talking about. Now, just recently, over the last week, the authors of the original trial had gone back and looked at not only LDL and the inflammatory marker C-reactive protein, but they looked at a whole bunch of measures that are known to be associated with atherosclerotic coronary disease, the hardening of the arteries. And almost in every case, these went in the wrong direction in that placebo group. They looked at it at 12 months and at 24 months, and it got worse over time.

Even this marker of inflammation... we all know inflammation’s not good, and it can actually cause risk of heart disease. And for these individuals who got the mineral oil, it went up almost 40% in the mineral oil group. It almost didn’t change at all in the fish oil group. This has started to unravel this trial and has raised this question... Let’s see, we’re in 2022. This thing comes out January 2019. It takes us this long to learn this. Thank goodness the authors went out and they really did this study. And they went out and said, “The truth is now we can’t tell whether this is effective. You need to do another trial.” That’s what they said in the paper, and the editorialist also endorses that.

Of course some of the trialists still believe in the med, still believe that it’s effective, but everybody’s saying that this has thrown a big wrench into the evidence about it. And only thing I think is like, “What can we do? We should have learned this faster. It shouldn’t have taken us this long. This drug’s been selling.” There was a whole big thing. The stock price is down because they lost the patent on it. So it’s gone generic, but there’s still a lot of people promoting it. And I would tell all patients taking it now that—

Howard Forman: We don’t know.

Harlan Krumholz: We don’t know.

Howard Forman: Let me ask you this, though. Mineral oil is used by a lot of people still for various treatments. And it’s sold over the counter. How do we get the answer to whether mineral oil might be very dangerous in ways that we’ve never considered?

Harlan Krumholz: Maybe there’s mineral oil and there’s mineral oil. This mineral oil was identified to mimic the color and consistency of the drug, what drug that they thought was going to be active. It would give me pause to take mineral oil as a means to improve my health, given that in this case, mineral oil, which... Obviously this is a big trial. They spent a lot of money. They spent a lot of time. The assumption was that this was going to be inert if—at best—and would be a fair comparator. Didn’t turn out that way. I don’t know if anyone’s listening who’s taking mineral oil. You might want to go to another placebo.

Howard Forman: It truly worried me when I kept reading more and more and realizing just how much we don’t know about things that we absolutely assume are non-toxic at the very least. At the very worst, mineral might leach out some nutrients or something, but we’ve never considered it for anything worse than that.

Harlan Krumholz: And who knows the mechanism? These people were largely on statins, maybe a blocked absorption. I don’t know what it did, but for these people in this trial, it seems like it was not neutral and, in fact, increased their risk of adverse events. Not proven, but it doesn’t look like it was good for them.

Howard Forman: You’re involved in publications, both as an author, as an editor in many different ways. I’d be curious to get your take on whether we have the right funding mechanisms in place to get the answers to the big questions we have. Just to put it clearly, we have a lot of innovation funded by the NIH, and we have a huge amount of innovation funded by clinical trials by vested interests, like pharmaceutical companies and biotechnology companies. But there’s so many questions out there that don’t have a financial motivation or incentive to get them done. And I’m wondering, how do we get the big questions answered?

Harlan Krumholz: I think it’s time for us to innovate the way that we do the funding of research. You and I have talked to our friend Zeke Emanuel, who we had on the podcast about some of these things. And the issue is that the way it’s configured right now is very conservatively. The study sections that sit and judge the value of and the importance of a particular application are geared in ways that I think don’t necessarily enhance the possibility that high-risk applications will be funded. They find all the problems with them. I don’t know what, but the culture of the study sections is that we’re really looking for ways that people have already solved, what are the major impediments? And this is a high likelihood of success.

That’s not a path towards innovation. A path towards innovation is a really great idea that’s got a lot of potential issues with it, and we want to give people the time to try to figure out how to make it work. I like the way that Howard Hughes Medical Institute manages things: they identify investigators, they give them money for a period of time. And then they ask them to show a portfolio of work when they’re done. And the reason I like that is a portfolio work, as I imagine it, is not just publications, but it’s evidence of impact. It’s evidence of progress. It’s evidence of evolution of thinking. It’s solving some of these problems. And if you can convince a team, when showing a portfolio of work, that the direction is meritorious, then you can continue on that path.

Now, of course, we have to be thoughtful about making sure that we’re stratifying so that we get young people and older people that we’re investing in. We have representative groups who are paying attention to inclusion and so forth as we think about who gets that chance. NIH’s got 42 billion dollars. Of course, a lot of it’s intramural, but a lot of it’s being sent externally.

I think it may be time to reconsider the approach that we’ve taken and take some risks on new ways of doing things. Then, as you know, I’m deeply committed to this idea of open science. So how can we hold hands and share the kind of data that we’re generating and try to help each other to be successful and move faster rather than a culture where I’m doing research, I sequester my own data. It becomes mine to harvest, and it’s my competitive advantage against other scientists, as opposed to the idea that the enemy is the disease. We’re trying to figure out how many smart people can we get working together to make progress about that for the benefit of patients. And then let’s figure out how to allocate credit if credit is important. But let’s not continue to march in a system that basically slows progress because of the way people are afraid to share and to be open with what they’re doing.

Howard Forman: I’m surprised and then at the same time not surprised that, in a four-plus-trillion-dollar system, where there are multiple actors that are enormously profitable, that we just still are not able to answer many big questions. And I will point out today, I hate to point fingers, but the health plan industry, the health insurance industry over the last 10 or 15 years has been very, very profitable. We’ve never actually had any expectation of them asking and getting the big questions answered. They will take advantage of the questions that have been asked by others, but they themselves don’t ask the questions, which quite frankly surprises me.

Harlan Krumholz: And I think there could be, you know, you say, “big questions.” I’m always also pushing for the small questions. When I was on the board of PCORI, the Patient-Centered Outcomes Research Institute, that was spawned out of the Affordable Care Act out of Obamacare to try to address the lack of knowledge we have about particular treatments. There was just a great conservatism about trying new things. I proposed to them, “Let’s do a hundred trials a year on things that people experience.” Pain, sleep, indigestion, abdominal discomfort. There’s a whole range of things. Shortness of breath. There are things that people feel and there’s a whole bunch of treatments that doctors are prescribing all the time. We’ve got no idea if they really work and for whom do they work and in what situation and at what dose? Because they’ve never been subjected to rigorous randomized trials.

And I just said, at PCORI, I think because these are about how people feel, we can be getting hundreds of people in a trial rapidly and trying to get some answers. And we could be looking at young people and old people and all sorts of different patient groups quickly to try to solve these problems. Many of these drugs are billion-dollar drugs, Lyrica—gabapentin—there’s just all these drugs that are being put out all the time for which there’s really... I wanted Tamiflu to be subjected to that kind of evaluation because Roche had... there were holes in what they had done at that time for influenza.

Howard Forman: Tamiflu is the oral drug for influenza.

Harlan Krumholz: For influenza, Tamiflu. Couldn’t get them to think differently about... and I also said, “If somebody has an idea from a academic institution, let them lead the intellectual part of the study, but don’t have them build the infrastructure to actually do the trial,” because what generally happens is each individual academic has to build their own infrastructure in order to do that. It’s cumbersome. They’re usually not highly efficient. It’s not what they should be doing. They should be asking the questions and it should go into a machine that’s ready to be able to help do this. And that should be a different competitive process about who’s going to actually run the trial as opposed to who had the idea to lead the trial. We just have to keep pushing for this, but I think we can’t be satisfied with the status quo. That’s the main message. Just because we’ve done it that way doesn’t mean we should keep doing it that way. And we should be open to doing things in different ways, in new ways, better ways.

Howard Forman: Yeah. Let’s hope.

Harlan Krumholz: Okay. Howie, let’s pivot to your part here. So what’s the things that have been on your mind lately?

Howard Forman: Yeah. I’m going to keep it short today. I do find myself.... It’s brief, but it’s frequent. I hear this from a lot of other people as well, just losing hope as we see women’s agency compromised, climate change fostered, gun violence getting worse, and seemingly greater divisions than ever before between our so-called blue states and our red states. But I do see green shoots of hope showing up. Popular opinion, which so often aligns with party, is showing signs of de-linkage on some key issues. Sixty-one percent of people in this country believe that women should have some, if not most, rights to abortion. Fifty-nine percent believe in sensible gun reforms going well beyond what we’ve actually just passed through Congress and signed into law. And 68% of Americans are somewhat or very worried about climate change.

I’m a believer in competitive markets, not just in economic and financial terms but in the market of ideas. Even as I am truly saddened by so much death and division around me, I can be heartened that the messages are, in fact, getting through. The more we can bring ideas, facts, data to people rather than talking just politics, the better we will be.

Harlan Krumholz: Absolutely agree with that. We need to get people away from... so just reflexively going with behaviors because they think it represents a signal of alignment with a particular ideology or a particular party. And that’s where I think we were with the pandemic, which is people are lining up on two sides simply because it identified them as being part of that movement or that group. I’d rather get people thinking for themselves, for discussing openly, on both sides, all sides and try to drive consensus within the country. This thing in Highland Park... I don’t know. Is that crazy that we should say like, “Who the heck should be buying assault weapons?” Let alone an 18-year-old who’s got a police record, has been investigated. It’s just beyond comprehension that we can’t come together on this.

Howard Forman: We all know the things that can help. We also know all the arguments that people will make and why they’re shallow, but we are stuck where we are. But I think, I’m seeing green shoots because I really do believe that people are starting to become more aware of how shallow those arguments can be.

Harlan Krumholz: I’m loving the green shoots, man. Let’s, let’s hope so because this country’s got to find some way out of this hole. You’ve been listening to Health & Veritas with Harlan Krumholz and Howie Forman.

Howard Forman: So how did we do? To give us your feedback or to keep the conversation going, you can find us on Twitter.

Harlan Krumholz: I’m @hmkyale. That’s hmkyale.

Howard Forman: And I’m @thehowie. That’s at T-H-E-H-O-W-I-E. You can also email us at health.veritas@yale.edu. That’s health.veritas@yale.edu. Aside from Twitter and our podcast, I’m also fortunate to be the Faculty Director of the healthcare track and founder of the MBA for Executives program at the Yale School of Management. Feel free to reach out via email for more information on our innovative programs, or you can check out our website at som.yale.edu/emba.

Harlan Krumholz: All right. So as a final thing here, how did you get to be known as “The Howie”?

Howard Forman: We’ve talked about this before. I’ll give you the very quick rundown. In and about 1991, I was a radiology resident at Wash U. I was waxing on about some topic, as you and I tend to do on the podcast right now. Somebody knowing that I was the representation of New York there and with a certain real estate developer in the news at that time finally making national presence known, somebody referred to me as “The Howard,” which was supposed to be a reflection of “The Donald.” At that moment in time, I said, “I’m not the Howard, I’m the Howie.” And I stuck with that over the years as a joke.

Harlan Krumholz: I didn’t realize the linkage between you and Donald Trump. This is really nice.

Howard Forman: Yeah, 31 years. It goes back 31 years. Don’t forget. You grew up in Brooklyn. You know about the Trump family from the time you’re seven years old. He was not somebody that I had great appreciation or quite frankly respect for.

Harlan Krumholz: That’s so funny. Health & Veritas is produced with the Yale School of Management. Thanks to our researcher, Jenny Tan, and to our producer, Miranda Shafer. Talk to you soon, “The Howie.”

Howard Forman: Thanks, Harlan. Talk to you soon.