Jerry Avorn: Countering the Drug Marketing Machine

Transcript

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

Howard Forman: And I’m Howie Forman. We’re physicians and professors at Yale University. We’re trying to get closer to the truth about health and healthcare. Our guest today is Dr. Jerry Avorn, but first we always check in on what are the hot topics in health and healthcare. And Harlan, you’ve been moving around a lot lately. What have you found out?

Harlan Krumholz: Well, Howie, you asked me to give you a few highlights from the American Heart Association.

Howard Forman: Yes.

Harlan Krumholz: They just completed in New Orleans. I was down there. I think perhaps the most futuristic study that was presented was the first in-human trial of CTX-310. I know that doesn’t mean anything to you. It’s a CRISPR gene editing for cholesterol.

Howard Forman: Oh, yes.

Harlan Krumholz: This article appeared in The New England Journal of Medicine and just 15 patients with difficult-to-treat dyslipidemia, high cholesterol, a single IV infusion. And at the higher doses, they were able to manipulate the products of the genome in a way that LDL cholesterol dropped by 50% and triglycerides by 55%. There’s no serious toxicity.

Howard Forman: We think that’s permanent, or we think that’s just a long effect?

Harlan Krumholz: We think that’s permanent.

Howard Forman: Wow.

Harlan Krumholz: So this is early, but stunning proof of concept that a one-time gene edit durably lowers atherogenic lipids, and it edited—here’s the technical part. So there’s this ANGE PTL-3 gene in the liver, and that’s what it’s editing, and those levels fell by 80%. But the downstream effect is that the LDL then, like I said, go down by 50%, triglycerides by 55%. It’s sort of like you’re not going to have to take statins anymore. You’re just going to go in and get a little snip.

Because here’s the idea, some people are born with low cholesterol and by the lottery of our genome, not everybody’s got that. And with the miracles of medicine, you’re going to be able to be like the person who was naturally born that way.

Howard Forman: Right.

Harlan Krumholz: And it’s amazing. It’s just amazing. So, let me keep going. So another was PCSK-9 inhibition for primary prevention. So everybody knows about the statins, those drugs are ubiquitous, but there are these other drugs that are being given by injection like Repatha, and these are PCSK-9 inhibitors, a little bit more upstream, and they’ve been shown to be effective for patients after heart attack and stroke. So, really driving the cholesterol down lower.

But Evolocumab was used, that’s one of these PCSK-9 inhibitors in 12,000 high-risk patients without prior heart attack or stroke, but with atherosclerosis or diabetes. And this was a group that people would have thought it wouldn’t have been worth escalating to this kind of medication, but over almost five years of follow-up, it reduced the first cardiovascular event by 25%, 6.2% versus 8%.

But this is, I think what’s interesting, people ask me all the time, “What’s the right target cholesterol level?” And of course it depends on you, what you want to do, what kind of risk you’re at, discussions with your doctor. But in the beginning, we said LDL should be less than a hundred. Then we start saying, “Well, you know, LDL for people with risks should be less than 75.” In this study, it took it down to a median of 45.

Howard Forman: Wow.

Harlan Krumholz: The safety was excellent, and I’m feeling now that I don’t know lower, better, 35, 45.

Howard Forman: And it’s also an oral drug, right?

Harlan Krumholz: Now, this is progressing. This has been an injection that’s going to be available in oral drugs now, and that was another study at the conference. So this and many more, it was an exciting meeting. Lots of interesting information, and lots of early actionables. All right, let’s get to Jerry, the big exciting interview.

Howard Forman: Doctor Jerry Avorn is a Professor of Medicine at Harvard Medical School, and founder and chief emeritus of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital. In addition to his work as a general internist, geriatrician, and drug epidemiologist, Dr. Avorn is the co-founder and co-director of the Program on Regulation, Therapeutics and Law, or PORTAL. He is also the founder and chief clinical consultant for Alosa Health, a nonprofit that provides academic detailing services.

Dr. Avorn pioneered the education outreach practice of academic detailing, which is now recognized internationally as one of the most highly cited researchers in this area of medicine and the social sciences. His research mainly focuses on medication use and its outcomes, the factors driving physician drug prescriptions and pharmaceutical cost-effectiveness. His most recent book, Rethinking Medications, out from Simon & Schuster just six months ago, is a riveting read about all that is good and bad about our drug regulatory process and industry.

Dr. Avorn completed his undergraduate training at Columbia University and received his medical degree at Harvard Medical School. He interned at Cambridge Hospital and completed his residency in internal medicine at the Beth Israel Hospital in Boston before joining the Harvard Medical School faculty in 1985.

So first of all, welcome to the podcast. I have the book here. This is a thick tome. This is a great read. It’s actually quite riveting. I mean there’s a lot of things in here that I teach. There’s also stuff I don’t teach about what is good and bad about the pharmaceutical industry. And I thought we could start off because you talk about this issue of academic detailing. I thought we could start off by just talking about that issue, which you address in the book, which really is at the junction of communications and the public and how do we properly prescribe and how do we use medications in a way that advances health? Do you want to explain what academic detailing is and why this was a novel topic 35 years ago?

Jerry Avorn: Sure. Thanks very much, Howie, and it’s great to be here with you and with Harlan. The idea that started all this back when I was really a resident was that the capacity to communicate the very best evidence about what works and what doesn’t in medicine and particularly around medications was being done superbly effectively by the drug industry but kind of lamely by those of us in academic medicine who, like the three of us, are deeply committed to just thinking about the very best evidence.

And as a result, there was kind of a disconnect between the very best that we knew about how to care for patients and average practice, which did not always measure up. And so I figured, why can’t we use the same communication strategies that drug companies use of going out to doctor’s offices, talking with us interactively, asking us questions, having appealing materials to show us and act more like sales reps than academics behind a podium. And that’s where academic detailing came from.

Harlan Krumholz: Jerry, I mean, people should know that I’ve admired you since I was in medical. You couldn’t have started as faculty in ’85. I graduated in ’85, and you were already faculty, I thought, when I was there.

Jerry Avorn: Let’s see, I finished my residency in ’77 and then right at that point joined the faculty and I started working on this right after my residency.

Harlan Krumholz: You were an inspiring teacher back when I was a medical student, and there was this academic detailing that so sort of excited me because you were showing us how you could be thinking independently about this and going up against the commercial interests. And it was something I’ve never forgotten, and I just wondered why it didn’t take off even more. And as I became a faculty and found out that what you’ve got to do is figure out what you want to do, but also who’s going to fund you to do it. I think I gained both some admiration for you in terms of finding some traction, but also who does pay for academic detailing?

I mean in a way like society, the government, I mean they should be interested in promoting sort of fair information about what people should be deciding, but it’s pretty hard to get anyone to get behind it with actual dollars, right?

Jerry Avorn: We’ve had some good result of this nonprofit that Howie mentioned, Alosa Health. And I sort of wish you had asked me this question a year ago, Harlan, because it would have been a somewhat happier answer. But we have managed over at Alosa to find support from a wide variety of sources. So for example, Aetna, which is not a source I would have expected, wanted to be a good corporate citizen at the height of the opioid epidemic. And they called me up and said, “We’d like you to use this academic detailing stuff to get doctors to not overuse opioids.” And I said, “What’s in it for you?” And they said, “We just want to be good corporate citizens,” and God bless them, that’s exactly the way it worked out for many, many years.

And they didn’t ask for anything in return. They didn’t want to have any say about the content. So that was one source. And health insurers sometimes rise to the surface in a good way. The CDC had supported a lot of work both by us and through state entities on opioid programs. The Indian Health Service has stepped forward and wants us to help them think about immunizations.

Harlan Krumholz: So one of the things that always impressed me about what you were doing was that it seemed to me that you weren’t coming out against the use of drugs. You were just coming out against… wise choices based on real evidence and not sort of tilting towards the use of drugs in the way that a commercial interest might want to promote a product, but rather promoting the best interest of the individual. How, when you were developing the materials, did you ensure that you were free from the kind of counter bias where you’re basically trying to say, “Well, we’re going to go up against what they’re saying,” as opposed to just try to say, “We’re going to try to be nondenominational, we’re just going to try to say, ‘Here’s just the facts’”?

How are you able to ensure that you were able to steer clear because it’s something tempting about saying there’s one side saying this and we want to be on the other side versus we actually don’t want to be on any side. We want to be on the side of evidence and just talk about choices. How are you able to walk that line?

Jerry Avorn: That’s a great question, Harlan. And I think all of us who are clinicians just want the best thing for the patient. And so whenever I would feel myself getting a little too contrarian, I would just think of Nancy Reagan and her completely idiotic statement about dealing with the opioid problem was just saying no to drugs, which of course didn’t work for the opioids and it doesn’t work for prescribing in medical practice. And I said to myself, “I never want us to be seen as having the attitude of ‘just say no to drugs.’” Medications are great; we all know how much they help our patients, and it’s only about use the right ones and use them a lot. Just don’t come out—

Harlan Krumholz: And appropriately for the place where the evidence is strong, right?

Jerry Avorn: You said it. Exactly. So really what we’re in love with is the evidence. And what we don’t really value or disvalue is the drug companies. If they’re on the side of the evidence, then we’re happy to say wonderful things about their products.

Howard Forman: And by the way, I just wanted for our listeners, the term “detailing” refers to when drug representatives come into doctor’s offices or hospitals and sort of pitch their drugs and they’re in the business of selling, they’re marketers and they are using evidence at times to try to compel sales, but they’re just selling. And that is what we meant by “detailing.” The term I used to use in class was “counter detailing,” which was including academic detailing and the insurance industry sort of pushing back and saying what is the opposite viewpoint from just the sales that go on there.

And so I just want our listeners to understand where the term “academic detailing” comes from. It’s really pushing back at the pure sales motivation of this industry. I don’t want to spend too much time just looking at the industry sales part of it because the FDA is a big part of the problem as well and they’re great.

The FDA has made enormous advances over the last 63 years since Kefauver-Harris passed. There are some things that have gone on that have just been fantastic, but in the book you multiple times talk about how accelerated approval and how this rush to get drugs out there can have really unintended adverse consequences. Can you say a few words about what you see as the good, the bad, and the ugly of the FDA?

Jerry Avorn: Sure. And the process you mentioned how we have accelerated approval really started out in 1992 with the very best of intentions, that it was the height of the AIDS epidemic and there was concern that there might be great products out there that could save the lives of people who were literally at death’s door from AIDS. And yet FDA had become so cumbersome in doing its very rigorous review that a lot of AIDS activists, one of whom was Gregg Gonsalves over there at Yale, took a firm stand and said, “Wait a minute. We need you to get these drugs out faster. It’s our lives that are on the line, and we don’t want a great drug that’s approved in three years and we’re dead.”

So the FDA did create this pathway for accelerated approval, which made a lot of sense at the time and still makes sense when used selectively, but the problem is that it has now become abused, I think, by industry, which has come forward and demanded accelerated approval for drugs that are actually pretty ineffective. And FDA unfortunately has succumbed to that pressure and has whisked drugs onto market. Particularly the example I talk about in the book is the drugs for muscular dystrophy that do not work, but they’ve managed to give them accelerated approval and then the follow-up studies just somehow don’t ever get done.

Harlan Krumholz: One thing I wanted to ask you was, what do you think about what the administration is doing about the direct-to-consumer advertising? I know they haven’t quite followed through completely on this yet, but there’s a movement towards saying we should really get rid of it. And as you know, there are only a couple countries in the entire world that allow it. Is this an area where you’re in alignment with what’s going on with the administration?

Jerry Avorn: Well, Harlan, I’m in alignment with the concept that you just stated. I’ve not seen anything but rhetoric thus far from the administration on that. They’ve said that they’re against direct-to-consumer ads, but I’ve not seen any concrete, effective steps to do anything about it. So I’ll be in…if and when they do anything.

Harlan Krumholz: So what would be your recommendation to them about what we should be doing about this direct-to-consumer advertising? And we talked last week, by the way, I was talking with Howie, it’s not just the drug companies, but now these telemarketing companies are like micro-dosing of GLP’s which is—

Jerry Avorn: Right.

Harlan Krumholz: ...no-evidence-based and stuff like that. I don’t mean to bias you, but I’m just curious. If you were in charge, what would you do tomorrow?

Jerry Avorn: I would love to go back to 1997 when we had laws and regulations that said you cannot advertise prescription drugs to consumers because the ideas and evidence are so complicated, you can’t cram it into a 30- or 60-second TV commercial. I don’t think we will ever get there somehow. And as you point out, Harlan, virtually every other country on earth except New Zealand, and even they don’t really allow it in the sense that we do. Every other country with wonderful healthcare systems—Canada, Germany, France, Japan, Australia. Literally every industrialized country does not allow advertising prescription drugs to consumers. So I would like to be like the rest of the world, but I’m afraid that the pressure to allow that advertising to continue is going to be too strong and will block such change.

Harlan Krumholz: Or at least they should allow equal time for academic detailing and let you go on following the commercial.

Jerry Avorn: PSA’s.

Harlan Krumholz: “Now, let me tell you the real truth about this.”

Jerry Avorn: Yeah, right.

Howard Forman: The Prescription Drug User Fee Act, which in the wonky world is called PDUFA. When I talk about it in class, I portray it as sort of glass half full/glass half empty. It was at a time of fiscal austerity, which seems almost cute right now, where the budget was something that people cared about and the legislation basically asked the pharmaceutical industry to pay a certain amount of money to support the staffers that would ultimately shepherd the application through the process. Rejected or not, I mean rejected or accepted and approved.

And I portray it that way and to me it seems like a good compromise legislation, though. I get the sense from the book and there’s certainly a lot of people in your side that feel like it’s just too close contact between industry and the regulator. That the regulator should not be effectively in bed with the industry and vice versa. Can you explain from your point of view, what would be the ideal situation for funding the FDA? Obviously, I guess with taxpayer dollars, but what would you do differently and why is it problematic in your opinion?

Jerry Avorn: Okay. I think a grown-up country ought to be able to have its federal budget fund its regulatory agencies without having to basically go on their knees to the industry that is being regulated and saying in effect, “We don’t have enough money to pay our staff. Would you please pay us?” And it’s now many, many millions of dollars a year.

Howard Forman: Yes.

Jerry Avorn: More than half of the budget of the salaries at FDA for the people who review drugs is paid for by the companies that they’re reviewing. That’s just not healthy, and it really is looking for trouble. I think we should have, again, another one of my idealistic kind of post-sixties boomer fantasies would be that the government would say, “If we want to have a regulatory agency, why don’t we pay it out of the federal budget and not have it paid for out of the companies that are being regulated?”

Howard Forman: But say a little bit more about the fear. So I get the fact that every five years Congress is effectively negotiating with the industry about what the fees are, and that alone seems problematic. But can you say a little bit more about the proximity between the regulator and the industry, whether it’s related to—

Harlan Krumholz: And Howie, just for listeners, can you just put this into bright relief? I don’t think a lot of people realize that the pharmaceutical industry is paying a portion of the FDA’s budget. Can you just make that clear to listeners because I’m not sure people really realize this and then go back to the question, Jerry, but ...

Jerry Avorn: Sure. Well, yeah, 50% or more of the salaries of the people, the scientists at FDA who are reviewing and evaluating drugs, comes from industry so-called “user fees.” And that is I think just a recipe for them feeling under the gun, knowing that if the industry were to take its user fees and go away, which they could at any point, then the FDA would be down half of its personnel budget and it couldn’t function. So it’s a kind of unhealthy relationship between the industry being regulated and paying the salary of the regulators. It’s kind of like having one of the litigants in a court case paying half the judge’s salary.

Harlan Krumholz: No, I think that that’s a really great way to say it. I just don’t think people realize, and when they call them “user fees,” I think it kind of sanitizes it. I mean, they’re actually paying subsidies to the people who are making judgments, not directly to them but to the organization, and it’s problematic. I wonder if you could share a little bit of your thoughts about conflict-of-interest issues with physicians and scientists. This is something we’ve struggled with. Of course there’s the Sunshine Act, where people can see what physicians are being paid by pharmaceutical companies, but there’s such a wide range of ways people are paid.

Sometimes it’s around research, and I don’t know how to get around that. I mean, a scientist wants to participate in research, the company has the money to support the trial. The amount of independence that that scientist has may vary depending on the trial. I mean, it’s hard to parse that. And then there are these things where people are giving talks on behalf of the drug company. And then there’s things where people are attending things where they sometimes can get paid for this. I mean, what’s your view about how we should handle now this side of it, the part about the doctors and their interactions and the payments that are going across?

Jerry Avorn: Right. Well, as you point out, Harlan, it’s a real gradient of things that are, of course, okay. Like if a doctor is going to spend 40% of his or her time designing and managing a clinical trial, then of course they shouldn’t be expected to do that as volunteers. So that seems to me to be perfectly all right. But you then depict at the other ends of the gradient, which are more worrisome, like a drug company pays a doctor to go to a course in which they essentially listen to a bunch of commercials for the company’s product. That is a different kind of transfer of cash that is much less savory.

I think we took a big step forward with the Open Payments Act that was part of Obamacare in which people said, “Look, at least patients and organizations deserve to know what their doctors are being paid by what drug companies.” And just putting that out there in the open, I think, was sometimes also called the Sunshine Act. That was a step forward. But yeah, when I set up our Division of Pharmacoepidemiology at the Brigham and at Harvard, I made a rule that I think is relatively unusual, which is that none of the faculty in my division would accept any personal compensation as consultants to drug companies.

We do actually receive grants and contracts from companies if they want us to help study a side effect. And that all goes through our hospital, and it’s very clearly demarcated in a contract. But I just decided, and we do the same at Alosa Health, that nobody in any kind of central role is going to be able to say that they doubled their salary by being a paid consultant to Novartis or Merck or Pfizer. And I think that’s a healthy way to do it. It’s a very unusual arrangement.

Howard Forman: There is a lot that we could say about the current administration and the FDA. There’s a lot going on, and I’m going to sort of table it for the moment, but I want to go back to the Biden administration, where there were multiple examples of the FDA seemingly doing things that were counter to the advice of their committees.

One of them you write very well about, the Aduhelm story, the Alzheimer’s drug story in the book. But one of the other ones that I’ve sort of defended, which I don’t think you talk about in the book. You talk about other disruptive drugs for Duchenne muscular dystrophy, but the specific case of ELEVIDYS, which is the more recent drug that has some marginal secondary benefits that may accrue to these terribly afflicted children. Catches my attention because the families are desperate, and they are absolutely looking for anything at that point.

And I was curious to hear your thoughts about during that time, I’m taking away the politics because we’re really talking about bureaucrats in a sense, people who were working with the FDA for a long time that seemingly overrode the advice of their committee members in an approval process. Can you give us a little sense about that?

Jerry Avorn: Sure. And Howie, you raise a really important point. This is not a Republican/Democrat issue. I think some of the problems that I write about in the book occurred in Democratic as well as Republican administrations. Some of those bad legislation was written by Democrats as well as by Republicans. Part of that is because the industry is one of the largest lobbying entities in Washington, maybe even the biggest. And as a result, they are doling out dollars to people on both sides of the aisle. So thank you for pointing out this is not a right/left issue. This is a kind of a graft/non-graft issue, if you want to put it that way.

And the example you cite is poignant because I cannot begin to imagine what it’s like to have a child with muscular dystrophy, and I, as a parent, would also be desperate for anything. But I think to come back to what you raised earlier about accelerated approval. A perfectly plausible approach would be to say that if there’s a drug that looks like maybe, maybe it’s going to help, and certainly the earlier drugs that were put out for this treatment that did nothing but make tiny changes in a lab test and did no good for the kids, those are off the table.

But what if you’ve got something that does get accelerated approval and may have a tiny benefit for desperately ill people with no other alternative? Great, put it out on the market. I think where we really fall down on this is that we let companies charge the full price of the drug. And as many listeners will know, full price is essentially whatever they want it to be. That’s kind of what drugs cost is what the manufacturers, unlike most other countries.... so I think a very plausible legislative action that most commonsense people would agree with is if a company only has a very slender bit of evidence that the drug works, put it out there, but let it cost only a very modest amount. And then if it shows that it does work, then you can jack up the price. But there’s a tremendous incentive now to market it at the full freight. And then as Sarepta did for some of its earlier muscular dystrophy drugs, not quite get around to doing the follow-up studies and it’s out there on the market costing millions if not billions—

Harlan Krumholz: Or billions.

Jerry Avorn: ...of dollars every year.

Harlan Krumholz: You know, Howie, we’re getting close to the end here. I just want to make a few comments about what it was like to be a student of Jerry when I was there. He was one of those teachers that he has a ton of charisma and so much positive energy, and you’d listen to him and you’d go like, “Why didn’t I see things like this before?” You sort of were socialized into thinking about things in a certain way. And then he would come in, and it was as if all of a sudden someone had just knocked you on the head and said, “There’s a different way to look at things and a different way to think about them.”

And you always felt that he carried himself with such integrity. He started something unusual at Harvard. I mean, to be able to start a division that was really looking at this standing up for the societal interest, it was really remarkable. And I just want to end with reading a couple of the Amazon reviews on the book maybe to get people interested in it. One person said, “It’s a must read, from an author who’s been present at Ground Zero throughout and is not afraid to name names. Happily Dr. Avorn is a gifted writer.” Another says, “An engaging and informative story... laid out the impact of misaligned incentives and flawed policies that affect medication availability in the US.”

Another one said, “His explanations give new insights to policies I thought I understood.” And another one, he says, “Jerry Avorn recounts bizarre processes behind the development, approval, and use of the medicines.” It really is. And by the way, we’re talking about medicines here, but I will say the device industry has similar issues, and it’s nice to have someone like Jerry try to stand up and give this perspective, and the book’s valuable. I just want to endorse it and I want to thank you, Jerry, for coming on because it’s just so great to see you, and it’s wonderful to have this opportunity to talk with you.

Jerry Avorn: Harlan, I cannot put into words how much I appreciate it. My eyes are moist, especially coming from somebody of your stature and accomplishments. It just means so much to me to hear those words of the effect that one can have on somebody in their formative years. God knows you’ve done fantastic things.

Harlan Krumholz: And never forgotten. That’s the thing. Howie and I talk about this. That’s why we care so much about teaching and mentoring too. Paying it forward from people like you where we realize that these things stick with people and can help them in their careers throughout. You did that for me. Thank you.

Jerry Avorn: I so appreciate hearing that from you, Harlan.

Howard Forman: And let me just also say three of our former guests, their careers would not have been possible if not for you. I mean, we’ve had Aaron Kesselheim, we’ve had Joe Ross, we’ve had Reshma Ramachandran—all three, their careers are built on the shoulders of you. And there are many, many more. And we’ve all said Gregg Gonsalves on the podcast, we’ve had a number of people who, in one measure or another, have built on your success and you forging in this area.

Harlan Krumholz: Inspiration. You’re an inspiration.

Howard Forman: So thank you so much for everything that you do.

Jerry Avorn: Well, in a very difficult year, your words mean so much to me, and I am so grateful for them.

Howard Forman: Thanks for coming on.

Jerry Avorn: Okay, thank you very much for having me.

Harlan Krumholz: Hey, terrific interview. I’m so glad we got Jerry on.

Howard Forman: Awesome.

Harlan Krumholz: It was so nice.

Howard Forman: And I want to correct the record for a second. He was promoted to associate professor in ’85. He was not appointed to the faculty in ’85, so you’re correct. He was in the 1970s.

Harlan Krumholz: And I don’t mean to step on you, but I just—

Howard Forman: No, you’re right.

Harlan Krumholz: I remember him. I was pretty sure he was faculty then.

Howard Forman: Makes sense.

Harlan Krumholz: But Howie, let’s go to another favorite part of the show for me.

Howard Forman: Yes.

Harlan Krumholz: What’s on your mind this week?

Howard Forman: So we have an infant botulism outbreak in the United States right now, and there are a lot of issues to cover for our listeners. And I think this is an important topic. First, infant botulism is relatively rare. It’s fewer than a hundred cases each year in the United States. And a consistent small but meaningful number typically occur from things like honey or improperly sterilized—

Harlan Krumholz: What is infant botulism?

Howard Forman: I’m going to tell you. I’m going to tell you, but it occurs from, it can occur typically from home-canned or -preserved foods or fruits, and outbreaks from commercially prepared foods are quite rare. And so the current outbreak has many novel elements. ByHeart Whole Nutrition infant formula, which is an organic baby formula, has been directly implicated in the current outbreak through some great sleuthing and clinical reporting out of California. And I mean that, and I’ll get back to that.

The Infant Botulism Prevention and Treatment Program in the California Department of Public Health is the national authority on these matters. They do all the tracking that the CDC and the FDA often rely on. Twelve states and 15 cases have been confirmed, but the numbers are likely going to be higher. There are additional cases that cannot be directly traced to the ByHeart formula and may just fall into the category of these sporadic exposures that consistently occur, as we noted earlier. Whereas initial indications were that only a few lots of the ByHeart formula were affected, the FDA subsequently clarified that all the formula should be off the shelves and not used. So they’ve been completely effectively recalled.

Of note, ByHeart only has one to two percent of the infant formula market. So this should not have the effect that we saw when Abbott had to shut down factories and distribution in 2022 and 2023. So just pointing out what the market looks like; this is not a big marketplace problem.

Infant botulism occurs—to your point, Harlan—when the infant ingests the spores of clostridium botulinum. The spores then germinate in an appropriate environment, and then the cells multiply and release botulinum toxin. Botulinum toxin paralyzes muscles at a significant dose. And in the case of the infants, this starts off with the most seemingly innocuous symptom of constipation and usually progresses to poor feeding, loss of head control, difficulty swallowing, decreased facial expression, and may lead to flaccid paralysis and respiratory arrests requiring mechanical ventilation.

Patients may require weeks in the hospital and symptoms can take weeks to develop, which makes it hard to trace the outbreak. In fact, the current outbreak probably began in August, if you can believe it. The good news is that awareness can forestall the worst symptoms at first medical presentation, and there is a treatment. And that brings us to the second part of the story.

BabyBIG, which stands for the baby version of botulinum immunoglobulin, is the name of the drug that was discovered and is made and distributed by the California Department of Public Health and their Infant Botulism Treatment and Prevention Program. It’s an immunoglobulin specifically targeting botulism toxin and has a well-documented safety profile and dramatically reduces the length of stay in the hospital for these seriously ill infants. And what is the price of this treatment? $69,300. Shipped directly from California at no additional charge.

I kid you not. I mean I’m being serious, but it’s still an extraordinary expensive drug. We’re going to put a link in the show notes about their website on infant botulism because I think a lot of people may have more questions. But I want to just point out, this is an example of public servants innovating and doing all the hard work.

Harlan Krumholz: How much did you say it is?

Howard Forman: I know. $69,300.

Harlan Krumholz: So what happens with an average American who needs to use this service?

Howard Forman: So this is absorbed into a hospital cost. The hospital basically, the pharmacy at your own hospital sends a fax or gets on the phone with California, they have 24 by 7 response. They make sure the patient has the botulism. You fill out the form, you show them the transfer code to make sure the money arrives via Bank of America. And $69,300 is the fee, independent of the size of the child because you may need a large or a smaller dose. It’s a one-time fee.

Harlan Krumholz: First of all, I just want to wonder who came up with 69,300? I mean, it’s not exactly a round number.

Howard Forman: Yes. So I really did some research on this and could not find an exact answer. But I believe that because we’re still dealing, even at that enormous price, we’re still dealing with only a few million dollars a year, it probably is the exact amount that they budget each year for the program. And so this supports that program at that cost.

Harlan Krumholz: Did you ever look and see what they do in other countries? I mean, this just seems a little bizarre.

Howard Forman: Yeah, I know. So there’s I think seven or eight other countries that order from California.

Harlan Krumholz: Really?

Howard Forman: And I do not know what other countries do. There is controversy about it. I mean there are some that say most of the children will do well with supportive measures anyway, but they will be in the hospital a longer period of time. And there’s even some studies that say because of the cost of this drug, it’s more expensive as well. But I’ll say that if it were my kid, I’d want the kid to have every last chance of reducing the risk of paralysis.

Harlan Krumholz: It just seems bizarre. I mean, wouldn’t a grown-up country have the federal government like the CDC just sort of stockpile this stuff and send it out as needed? It’s just amazing.

Howard Forman: It’s an orphan drug. They’ve decided to distribute it. I think if the CDC did it, we would have to still fund it at eight or 10 million dollars a year.

Harlan Krumholz: No, I know, but if it wasn’t for California, we wouldn’t even have it.

Howard Forman: Oh, I know. And it is bizarre. When you look at the order form, and again, we will put it in the show notes. When you look at the order form, it’s like, “What is the account number that you’re transferring it from? Do you promise it’ll be transferred?” I mean—

Harlan Krumholz: Oh my God.

Howard Forman: They’re doing the correct fiduciary—

Harlan Krumholz: Meanwhile the parents are out of their minds trying to get this for their kids.

Howard Forman: I know, absolutely. Well, it’s the hospital that has to do this.

Harlan Krumholz: No, I know. But it’s still somebody in the hospital has got to approve $69,000.

Howard Forman: Yes.

Harlan Krumholz: Thank you, Howie. Another fascinating aspect of our healthcare system.

Howard Forman: I know.

Harlan Krumholz: Brought to you by Howie Forman. 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 keep the conversation going, email us at health.veritas@yale.edu or follow us on LinkedIn, Threads, or Twitter or Instagram, where we have a new account coming online.

Harlan Krumholz: And give us feedback any way you want, and we always enjoy looking at it. Actually, somebody just suggested a guest to us this week. We always consider the suggestions, and we’re always open to outreach.

Howard Forman: Health & Veritas is produced with the Yale School of Management and the Yale School of Public Health. To learn about the Yale SOM’s MBA for Executives program, visit som.yale.edu/EMBA and to learn about the Yale School of Public Health’s Executive Master of Public Health program, visit sph.yale.edu/EMPH.

Harlan Krumholz: And we want to share a little gratitude for our superstar undergrads, Gloria Beck, who is here with us today, Tobias Liu, to our amazing producer, Miranda Shafer, and for me to be able to work with the best in the business, Howie Forman.

Howard Forman: I appreciate you, Harlan. It’s a great episode.

Harlan Krumholz: Talk to you soon, Howie.

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