The Peter Attia Drive - #75 - David Light: Zantac recall due to cancer concerns – what you need to know

Episode Date: October 14, 2019

In this episode, David Light, CEO of Valisure (the company which alerted the FDA to the Zantac cancer concerns), explains the story behind the recent recalls by manufacturers of ranitidine, a common heartburn medication, sold under the trade name Zantac, due to a potential link to increased cancer risk. David breaks down all the evidence, the role of his unique pharmacy company which tests all its drugs before being dispensed to consumers, and the reason behind the FDA’s tempered reaction to the alarming study results. David makes the argument that Zantac/ranitidine is an inherently unstable molecule which explains the grossly excessive amounts of NDMA (a probable human carcinogen) as opposed to just a contamination for which there could be numerous causes. Finally, David and Peter both provide recommendations for what to do if you or someone you know is currently taking Zantac/ranitidine. We discuss: The impetus for starting Valisure, a unique online pharmacy that tests all its medications [6:45]; The story behind the recall of valsartan, and the role which Valisure played [24:30]; Testing Zantac: The shocking results from Valisure’s initial testing with major potential cancer implications [36:00]; NDMA - the probable human carcinogen found in Zantac/ranitidine [48:45]; The epidemiology question: Are we inferring too much from epidemiology? What can we take away from the existing studies? [53:30]; The staggering results from the 2016 Stanford study, why it didn’t alarm more people, and how Valisure found the missing biological link [1:01:30]; Alerting the FDA, the FDA’s tempered response, and question of contamination vs. inherent instability [1:07:30]; How confident is David that the elevated levels of NDMA being found in ranitidine are not due to instrumentation, human error, or temperature contamination? [1:24:15]; The massive risk being taken by the FDA by not doing more to keep ranitidine away from consumers [1:25:15]; If someone is taking Zantac/ranitidine, what should they do? What else do they need to know? [1:27:45]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/davidlight/ Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other

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If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. I guess this week is David Light, the CEO of Valisher, which is an online pharmacy and analytical laboratory that tests the drugs at dispenses. As some of you may have heard on September 13th of this year, a citizen's petition was filed by David's company to the FDA, requesting the immediate attention to and potentially removal of a very common drug called Xantac, or Renidine from the market. Based on a lot of analytical horsepower that they had thrown at it, suggesting that Xantac

Renididine in its generic form was unstable and it decayed heavily into a carcinogen known as N-D-M-A. The details of this, obviously we discuss in the podcast, but they are quite staggering when you consider the magnitude at which this decay occurs and therefore the level at which people could be exposed. Now, the purpose of this episode, of course, is not to scare people, though in the end, I do something I rarely do, which is make a recommendation, which is if you are playing this through the lens of standard risk analysis,

the better thing to do is to probably at least yourself stop taking this drug, even if the FDA, which at the time of this recording, has not asked for a withdrawal, either voluntary or otherwise. It's important to note that at this time, 30 other countries, including Canada, many countries in Europe, the Middle East, have done that, have gone to the step of saying, this drug is off the market until we clarify what these issues are. In the first 20 minutes of this episode, we get into the background. And it is kind of important to understand David's background in chemistry

and the background of how this company became formed and what the impetus was for that. We then get into kind of their first real insight that they made at the public health level, which was the discovery of a carcinogen in a very commonly prescribed blood pressure medication called Valsartin. And in this case, it was a contaminant, meaning it was not unique to the entire drug, but only to certain manufacturers. However, the majority of this episode is devoted to the discussion of Xantac and Renididine. I don't need to really say much more. I think the episode speaks for itself, and it is timely. And again, if you've never taken Xantac, don't care about this.

Great. Might not be an episode for you, but if you know anybody who takes this, and at last check, 15 million prescriptions of this were filled annually in the United States. not be an episode for you, but if you know anybody who takes this, and at last check, 15 million prescriptions of this were filled, annually in the United States, and when you consider the over-the-counter being easily two to three times, the number of that odds are,

if you're listening to this, either you take Xantac or know somebody who does, at the very least, you'd wanna pass that onto them. So without further delay, please enjoy my conversation with David Light. David, thank you so much for making time to speak on a Saturday evening. My pleasure, likewise. If the listeners wondering why we're having a discussion on a Saturday evening, it's in large part, I suspect, because this is kind of a timely issue and so many of my

podcasts are scheduled out months in advance, but this was something I didn't really feel should be put off for several months. So I thought if you were willing to talk on a Saturday night, then I would too. Thanks for having me. Yeah, yeah. So let's spend just a couple of minutes on some background before we jump into the real meat of this discussion. I first learned about you

through a woman named Catherine Eban. Do you know Catherine? Yes, I do. So you may know that I interviewed her a couple of months ago and it was honestly for me one of the most upsetting interviews I've ever done. I guess I haven't interviewed enough bad guys in my life, not the Catherine's a bad guy but she was really talking about a story that was for me very disheartening, but I think also for virtually every listener kind of just blue people away. And I knew that the moment we published that podcast, which we did in probably early September, that there was going to be a lot of questions coming out. A lot of people were going to wonder what the implications of this were. And even just in my own little tiny bubble of a world, which is my very small medical practice with fewer than 100 patients, the implications have been pretty significant. We have basically

changed the way we do everything in terms of we now exclusively work with one pharmacy that pharmacy, while not able to do what your pharmacy does, and we'll talk about that in a moment, they're able to do something pretty darn good, which is at our discretion and without any hesitation, they will dispense exactly which medications we want. So branded when the patient is willing to pay for branded and if generic, then they are able to do what we do with them. Actually, we do the heavy lifting, I suppose, which is we go and look at the company that makes the specific generic and look to see if there's been any interaction with the FDA.

Now, that doesn't guarantee that we're safe, but I think it's reducing our odds a lot. But let's now talk about what you do professionally and within the pharmacy space, and maybe a little bit about how you even decided to do that. Sure. So, Valisher company that I co-founded and the CEO of is an online pharmacy, but it's also attached to an analytical laboratory. So, it's actually the first pharmacy, whether online or not, that is chemically validating samples from every single batch of every single medication that comes to our pharmacy. and screening out those that have problems and quite a few

do. And then for our patients, only dispensing those that pass. And we also dispense it with a certificate of analysis and very much like nutritional information. I mean, you don't buy food without looking at the nutrition label and seeing what's in it. But where is that for your medications? So in that certificate of analysis, we're actually giving the information of what we've actually analyzed for that particular batch of that particular medication. Now, a lot of people might be saying, well, David, why is that necessary? I mean, didn't the FDA already do that? Isn't the point of having the FDA that when I go into my pharmacy

and I'm dispensed, my blood pressure medicine, isn't the FDA's seal on that in the same way that the USDA's seal is on the chicken breast that I buy at the grocery store. So the FDA seal is on it, but I think a lot of people are rather shocked to understand that the FDA is not doing chemical testing on the vast majority of medications that are out there. The testing that is done sometimes and some of the batches are done by the manufacturing companies themselves,

which these days are almost entirely overseas, 80% of drug products in the United States are manufactured in either India or China, and then self-reported to the FDA. So there's obviously a lot of options for problems and cracks in that kind of self-reported to the FDA. So there's obviously a lot of options for problems and cracks in that kind of self-reported system. These days, you hear a lot about self-reporting system problems with aviation and the Boeing 737 MAX.

Airplane exploding is obviously a very visible component of something going wrong, but your medication's going wrong is actually very hard to see or to find out. And then not to mention, as you mentioned, Katherine, even before she did a very deep study of all the fraud that goes on when there's a self-reported mechanism. So we definitely saw that and said, this is not acceptable for how we would want pharmacy to be. Valisher actually started with a good friend of mine from college

that called me up one day. It was telling me about all these problems he was having with his anti-convulsive medications. Essentially, every once in a while, he'd refilled and just have this terrible month get all these side effects and relapses sometimes and just felt very different from how he felt otherwise. And he talked to his doctors,

and he's got some great doctors in the doctor's tone. Listen, this system is problematic, 90% of what's out there these days is generic, and it can be made from all over the place, and I think as you're kind of alluding to in terms of working with one pharmacy, just switching from generic to generic could be problematic.

They're formulated differently. They're allowed to vary in their bio-equivalence by 45% from one another. So our high level solution for this was we want to actually have medications chemically tested at the end of the supply chain in the United States where it matters most and test them, see what's actually inside of them and then decide if we want to actually dispense them. Forgive me for being skeptical because while today this sounds like a great idea, how long has Vallejo been around?

My friend Adam and I, so Adam was the one that called me up with this issue. We started the company in 2015 and originally looking at this as a technology problem. A potential reason why nobody's been doing this before is that the technology can be very expensive and cumbersome and really just tailored to one or two drugs when you do this in a manufacturing plant and in pharma companies. But if we wanted to do this in an economical way and in the supply chain, there's kind of this technology gap. And so we actually spent a number of years developing core technology, a spectroscopy-based approach, essentially applying lasers to pharmaceutical analysis, so that we can do some of the most difficult and costly components of this analysis in a much higher throughput, much easier to use way while still maintaining a high precision.

And after a couple of years of bootstrapping this whole thing and putting a lot of our own resources into developing the technology, we achieved it. We got ISO accreditation on the system itself. That's the international organization for standardization. We filed patents. We kind of thought of this as the traditional biotech model, which is where the kind of industry that I'm from, where a lot of the original founders of Alisher are from, and we went and talked to the industry, the big distributors and pharmacies and manufacturers, and it was a very odd discourse because all these major players were telling us, yeah, you know, there are a lot of problems in the system and it looks like the problems are getting worse, but it's not our problem.

As always, ended up being somebody else's problem and we also realize that there's actually seems to be disincentives. The established industry actually looked closer at what's on the shelves. They may not like what they see. And so this was really around now end of 2017, early 2018. That's when we decided,

we actually have to attach this to a pharmacy. So we already had the credited laboratory, controlled substance licenses, and everything else around a laboratory, and then we built out the online pharmacy component. And that launched just about a year ago. And when I was referring to my skepticism, I guess what I was really getting at was,

in 2015, if you had pitched this idea to me and said skepticism, I guess what I was really getting at was in 2015, if you had pitched this idea to me and said, Hey, I got this idea, which is we're going to actually test individually every single drug that gets dispensed. I would have said, gosh, that doesn't really sound like it's a significant enough problem. I mean, there's two issues with it. Is there enough demand for it? I would have said no. And secondly, the scalability of that strikes me as cumbersome and difficult.

So maybe to give me a tangible example, if my doctor called me in a prescription for 90 tablets of alopeurinol, 300 milligrams of alopeurinol, 90 tablets to last me for three months, would you open a batch of alopeurinol that you got from your generic supplier and let's say that batch that you got from your generic supplier? Let's say that batch that you got wholesale, how many tablets would that contain? So you're actually getting the exact root of the business plan of how to make this economical is that at Valasher on the pharmacy side, unlike most other pharmacies that are going to be buying every day or every week and are kind of just constantly looking for the cheapest possible source and therefore also not having a lot of inventory, we buy large

batches. So, we'll look six months out usually at least to buy a lot of that medication up front. So we have a larger batch of it so that when we sample it, when we do all of our analytics, obviously that adds some cost, but that cost is amortized over the larger batch. So per pill that you're buying from us, it's not adding a whole lot of cost to us, especially as we have proprietary technology that also allows us to do this in arguably some of the cheapest possible ways.

And we really optimize for it. But we're obviously making less money than your standard big name pharmacy that's not doing any of this. But you're seeing that a lot in the world of online pharmacy these days, there's all these kind of value ads that are coming out there. So, whereas our competitors are working on spending money on specialty packaging

or sending chocolates with your birth control pills that cost money too. Instead of spending money on that, we spend money on analysis, and it obviously cuts into the overall profit margins, but we're still able to make money as a company and offer this what we certainly believe is a really critical service of analysis on that batch of medication.

I don't know if you ever heard the podcast with Catherine, but I believe in that podcast, I tell a story about sort of the first time it occurred to me that generics, there might be something wrong with a generic and it was several years ago and it was a patient who I had prescribed Crestor, which of course got filled as Resuvistatin, which is not uncommon at all. That's the generic version of Crestor. He he had previously been on a Torvistatin, the generic version of Lippitore, but there was just, there was something I didn't like.

There was a blood biomarker I wasn't happy about, and I thought before we abandon a statin altogether, let's give it one more try. So we put him on an equivalent dose of Rizuvistatin, which is usually half the dose. So I think if he was on 40 of Litor or a Torvistetin, I put him down to 20 of Crestor, which got filled as Rizuvistetin. Eight weeks later, I get his blood back, and he's back to his baseline level of APOB,

which is the thing that I'm tracking, suggesting he's not taking his medication at all. Now, I'm not a brow-beating doc, so I'm very straightforward with my patients. I just say, hey, did you forget the take-em? Did you run out like a month before the test or what was going on? He said, because, and if that were the case, he would simply say, Yes, I just, my patients are very transparent. And he said, No, no, no, I take a take this thing religiously. And I'm scratching my head and thinking, We know that he is statin responsive. So there's something about this batch that could be different. So I just had my team call in and insist that we get the branded version.

We got it. He took it. It worked. I sort of forgot about it. That type of thing happened a few times over the last few years. And then of course, reading Catherine's book, I was like, oh my God, the lucky times are the times when we see the drug, and it has a very obvious measurable response in a biomarker. But then there's a whole other class of drugs for which that's not entirely true, drugs like blood pressure medications, or seizure medications, or antibiotics. In fact, most drugs do not fit in the camp of a very clear bio marker. So, when you set out to do this, again, based on your friend's experience,

what did you expect to find? Because at the time you guys started, Catherine hadn't done her complete investigative watershed exposé of the mass fraud coming out of India and China. So, did you think this was a needle in a haystack problem, but you just wanted to give people peace of mind? Or did you think this was a much larger systemic issue? Actually, when Adam called me about the issues that he was seeing himself with anti-convulsive medication, I mean obviously I was concerned about his own health, but for a business, I definitely wanted to understand, is this something more pervasive and I myself was not on any medications

at the time. So I had no personal experience to relate it to and figured, hey, as a scientist, myself, let's look at the literature. And there's a lot of literature out there, especially in certain areas, like anti-apileptic drugs. It starts talking to neurologists, oftentimes especially psychiatrists that see a lot of these issues between brand and generic, between generic and generic substitution. And I recall even back then that one of the papers that I looked at was a Harvard Medical School study that had almost 2,000 patients and showed simply the act of refilling your anti-epileptic medication was associated with an over twofold increased chance of getting a seizure. Now, like, wow, as a scientist looking at this, like, this sounds really serious,

and especially in a kind of a class of medication where it's so clear when your medication is off, you get a seizure, but to your point, this must be happening in all sorts of medications where it's less clear. And once you really start talking to a variety of different doctors, you start hearing it a lot too. It seems like a lot of doctors have at least suspected it as a problem or have similar stories as you talk about.

I know certainly in Katherine Eben's book, Bottle of Lies, she talks to a couple different doctors from the Cleveland Clinic that have seen it in your heart failure medications and diuretics. And it's very hard to actually pinpoint the exact problem and nobody's really looking and analyzing. So what we thought in the beginning was that the very least in certain key areas like antipyletic drugs, like antideants, and various others that are very big markets, and a lot of people seeing these issues, that at the very least there,

we could have a lot of impact and start looking. But to answer your question, did we think the problem would be as pervasive as we're already seeing? I don't think we would quite predicted just how much we'd be finding and how quickly and how the engagement of all this is just really, really increased in certainly in the last few years.

But if you look at it, there is a huge problem with well, butrin and pubropion back in the late 2000s, 2007, 2008. There's a lot of these cases that have happened. And I think a big part of what we set out to do and what we're actually hearing from these doctors now is that there really just wasn't much that a doctor could do. It's either brand or generic. Brand, you tend to trust more, but can't obviously afford very often.

And then you have generic that there's less and less trust in, but you can afford. And essentially set out to create a validated generic. Something that has actual chemical validation behind it, and you can still afford same prices, generic that you'd be buying anywhere else. Was the business model, and more importantly, I guess your hypothesis, that this was a problem confined to the generic market market or did you also intend to check branded drugs and did you by extension then assume that branded could be susceptible

to the same problems? I think that the general thesis was that this is probably worse in generics than in brand. However, we had nothing to really back that up and obviously the data just didn't exist period for these kinds of things. So our intention was always to say, we don't know exactly where these problems are gonna be fun and we're not gonna make any assumptions ahead of time. Just everything needs to be independently tested

at the end of the supply chain before a patient gets it. And David, one last question really and as far as background goes, you've alluded to the fact that you have a scientific background, but specifically, what is it about your background that allowed you to come into this space and actually innovate? I'm a molecular biologist by training at Yale University and I spent most of my working time in the field of DNA sequencing so in biotech essentially developing complex tools

for analysis of complex problems. I spent eight years, most recently, at a company called Ion Torrent, where I was one of the original technology founders there and head of chemistry R&D. And we essentially had this concept that we would sequence DNA on a microchip. It was based on some papers that we spent millions of dollars proving was just noise, but luckily we had some other ideas in mind and had an amazingly innovative group of people there, even early on, that were able to make it work. And Ion Torrent is now the number two DNA sequencing technology in the world. So myself and some of the other key developers, even at Ion Torrent and folks that I've worked

with before, I think we're well positioned to develop some new technology, which is, again, how we saw this problem originally being solved is something that we can develop and then just plug into the existing system. And that's what we started off doing. And then brought in some more folks to enable the pharmacy side to work as well. All right. So let's fast forward to a little over a year ago. It's the summer of 2018. I actually get a call from one of my patients,

the only one of my patients who takes a medication called Valsartin, which is a drug called an angiotensin to receptor blocker. It's a drug that we use in certain patients with high blood pressure. And in particular, this is a patient who all the other boxes had been checked. Otherwise, a very healthy guy, but just couldn't get the blood pressure where we wanted it. So here he was taking this medication. And he said, Hey, guys, I saw something in the paper

today about some of these things being withdrawn. Should I be taking it? Tell me a little bit about that and your involvement in that. So Val, Sarton and Lois Sarton and various other our medications are Sarton medications that have been recalled over the last year. I think are unfortunately a very clear and visible case of how the system can go wrong and how many cracks there are in it. The fact that this global supply chain is a self-reported,

has a lot of visible fraud that's happened in the past. And really what happened with Valsartan was there was a manufacturing change to save some money in China or other places overseas that are making the variety of these different active pharmaceutical ingredients. And by having this manufacturing change, they were creating all sorts of impurities. So, these impurities themselves being extremely potent carcinogens. One of them that I'm sure we're going to be talking more about is NDMA. And I chose to dimethylamine. It's actually talked about as a probable human carcinogen, but you have to keep in mind that's only because you can't ethically have a study where you give humans a carcinogen.

And the data in animals is extremely clear. It's been studied since the 1950s. NDMA is literally one of the best studied most potent carcinogens known to man. It's actually used as a control to induce cancer in rats. If you're doing a clinical study and want to make absolutely sure that a rat's going to get cancer, you give it NDMA. So this was one of the contaminants that they were creating in this process that they obviously didn't do the proper quality controls that they were reporting to the FDA and went all over the world and this happened for years. It was only detected years later,

I'm sure just kind of randomly, and then as people were looking more into it and it actually oversees, countries started recalling it, eventually it was also recalled in the United States, and it was obviously a very real problem that even continues today. So we're talking about it in 2018,

some of the 2010s when it started, the most recent recall in low sardine, I think was like a week ago, and we're in October, September here of 2019. And this continues to be a pervasive problem. Before we leave this topic and get to what we really want to talk about today, which is Zantak and Renitidine, what is the take on message for patients and physicians, either taking or prescribing respectively ARBs, this class of drug? It certainly seems like the problems even there are not over, especially the fact that there's

been recent recalls even now. We at Valachir trying to be very proactive about this whole space. We incorporated this kind of carcinogen analysis earlier this year. I mean, we just launched the pharmacy at the end of 2018 towards the beginning of 2019. We added nitrosamine assay and incorporated the FDA recommended protocol for analyzing for NDMA

and other carcinogens and impurities. And we wanted to not just look where everybody else is looking, we also looked at other seemingly obvious places to look. So when this manufacturing change happened, what the change was is they changed solvents and they started using this solvent called DMF, dimethylformal-mide. Can you explain to people, David, what a solvent is and why it's necessary to make a drug

or do most organic chemical reactions with solvents? Sure. So, a solvent is basically something that you're dissolving different components of chemistry into in order to make a reaction. You could think of it like cooking. If you're going to make a soup and you want a whole bunch of things in it, you're solvent is essentially water. Or even if you're cooking an egg, for example,

there's so many different ways to cook the egg. But if you change your solvent, if you change how you're essentially cooking that egg, although it's still an egg, all sorts of other things can happen. So what they really did in this case of Valsarten was they might have been cooking the egg in in water for a long time and then all of a sudden they decided to switch to oil. If you've ever fried an egg, obviously it tastes different than if you boiled the egg. And those differences are because of all these side reactions and side products that are happening that give it different flavors and all sorts of different properties. But yes, it's still an egg, so they were still making Valsartin,

the key ingredient they were trying to make. But there was just so much happening on the side that they apparently were not doing the proper controls of trying to find out what's happening there. And NDMA, true that it's hard to look for every possible contaminant that there exists. But again, NDMA has been well studied, has been talked about as a problem

pharmaceuticals since at least the 70s. So seemed like a fairly obvious thing to look for. And for us, when we started seeing all this, of course, we were going to look for NDMA and DEA and a few of these other common carcinogens that we're being talked about as byproducts of this manufacturing change, but we want it to also look for this new solvent. I mean, if you're going to cook the egg in oil now, there might also be oil still on that egg. And that solvent, the DMF dimethylformamide, is itself a probable human carcinogen.

It's in the same class of a carcinogen as NDMA. And this is a categorization from the World Health Organization and the International Organization for the Research Cancer. So we started looking for that too. And as soon as we started looking, we found it all over Valsartan. We found two thirds of the manufacturers that were making Valsartan that we actually

looked at their batches at the time, had hundreds of nanograms to over a hundred thousand nanograms of this DMF contaminant, which is a probable human carcinogen. And so we put together an FDA assistant petition and filed it with the FDA saying, listen, obviously NDMA is a problem, and there's other problems out there that are certainly a good idea to continue looking at. But the solvent itself is carrying over in this system. And whatever these companies are doing to try and clean up their process, they're apparently not even cleaning up the solvent. So it certainly underscores the importance of checking everything and also checking every single batch. I mean, we had

manufacturers that were clean sometimes. And then another batch had not only very high levels of DMF, even had levels of NDMA that were violating the FDA rules. So it certainly underscores the pervasiveness of the problem in certainly in certain areas. David, some people who are familiar with the biotech industry will have heard a term GMP. Do you want to explain what GMP means and what the implication is for something that's manufactured according to that standard? Yeah, GMP standing for good manufacturing practices, anything that's under FDA purview that touches the manufacturing process is required to be under GMP. And it's essentially hundreds of

documents and systems that are in place in order to make sure that things are very well documented and done consistently and any errors or problems or manufacturing changes like changing over your solvent, checking for contaminants, these kinds of things are all expected to be part of the GMP process. And when you're following the whole GMP system, then it's supposed to catch these kinds of issues. But this is certainly a very robust system. However, it's predicated on the concept that you're going to self-report it to the FDA. And that when the FDA comes in inspects, they're going over these documents, they're not checking the chemistry of what's actually in that pill. Is the implication here then that, well, let me just ask the question more directly, is there any evidence that any of the companies involved in the production of angiotensin receptor blockers, drugs such as Valsaritan and Lossaritan, actually're criminally negligent. In other words, saw that their chemical

processes yielded molecules that exceeded the acceptable limits of various toxins and failed to report it. Or do you believe the evidence suggests that rather all of this was simply negligence and oversight? Honestly, I haven't looked at that kind of evidence well enough to answer directly. I would say either is certainly possible. It could have been maliciously covered up by a manufacturer, or it could just be that they were saving a few pennies per pound of these kinds of solvents and just didn't bother to look. I definitely don't have that answer.

I don't want to get too far down this rabbit hole because, like I said, what I really want to talk about is the most timely issue here, which is the Renitating and Xantech one. So I apologize. I keep saying we'll get to it. And maybe we can park this question. But it's a broader one, which is why do we have the FDA if not to do this, if not to be the one to ensure that every pill that goes in a person's body comes from a batch that has a certificate that demonstrates not only what's in it, but what's not in

it. Yeah, look, what the FDA is there to do is a lot of things. I know we're talking a lot about the oversight of drugs that are already in the market. Obviously, a lot of what the FDA is doing is looking at new drugs and a billion dollars that goes into developing something new. I think the bottom line is that with limited resources, there's only so much you can do. And a lot of what the FDA oversight is about

is going through that GMP process and looking over a bunch of paperwork that's being self-re self reported by the industry. And that obviously has limitations, which honestly the FDA itself admits in a 2015 white paper direct from the FDA, A, they're saying there's an unacceptably high occurrence of problems.

And B, the FDA was saying that there's no formal means for quality surveillance except through inspections. And inspection findings have not been a reliable predictor of the state of quality. Those are pretty much direct quotes. So we at Valisher and the original founders saw this as further underscoring of industry should be stepping in and doing more. Why don't we actually analyze every single batch of the supply chain. FDA doesn't seem to have the resources to be able to do something like that,

but in the core of a new business model with some new technology and everything else, so we thought we could do it. There's more I want to talk about on that front, but I think I'm going to save it until we get to the end of our discussion. So let's start talking about this drug Xantac. So Xantac, the generic name for that is Renididine, has been around for quite some time. I can't tell you how long it's been, but I certainly know it's been more than 20 years because it was among one of the most commonly prescribed drugs

that I would have written prescriptions for for patients in medical school. It's an H2 blocker, which means that's one of the three ways that you can reduce the acid secreted by the stomach. And this is one of those ways, is you can actually block the H2 receptor on the type of gastric cell that makes hydrochloric acid. And therefore, it became a very popular drug, not just for people with heartburn, but

more importantly, or at least as importantly, I suppose, even patients who didn't have heartburn who were undergoing Hospitalization in whom one needed to reduce the burden of insult to their gastric lining. So I don't even have the stats on how many people take Renitidine or Zantec in the United States. Do you know those numbers David? The prescription Renitidine in 2016 was roughly 15 million, I was in the top 50 most prescribed drugs, and obviously that's certainly a small percentage

of the overall use being that it's largely used over the counter by the brand's antac or other various generics, practically, any pharmacy that you used to go to, it's not there anymore, but pretty much every pharmacy had their own versions and it's one of the most common over-the-counter medications used, certainly, by millions of Americans and folks over the world.

Yeah, I've been fortunate in my life to not have heartburned more than twice a year, but those two times a year, I sure took myself some Renididine. One other thing to mention there that was certainly a particularly high-concerned to us, is that the safety profile of Renididine. One other thing to mention there that was certainly a particularly high concern to us is that the safety profile of Renididine was considered so high that is one of the only drugs prescribed to women while they were pregnant and given to infants for similar stomach issues.

Yes, my third child had reflux and he took a little liquid elixir of Renididine for about three months when he was little, and I also remember from doing my rotation in pediatrics, that was not an uncommon thing to do. So tell me how you became interested in Renididine. In early 2019, when we're obviously responding to all these issues as we've just talked about with Valsart and other of these blood pressure medications that had these carcinogen issues. It was obvious that we needed to incorporate that technology and then be proactive. As we talked about not just look for NDMA and the standard carcinogens that are what

we're looking for, but look for other common sense molecules and carcinogens at the same time, but also the same time, not just look at the blood pressure medication. So our whole concept, of course, it vouchers, analyzing from every single batch of every single medication. And ironically, renetting was pretty high in our list to go through the system because that same friend of mine, Adam, his infant daughter also got a prescription for that elixir of Reninidine, the syrup form. And as soon as we put it through the machine, following

the standard FDA protocol at the time, we were just floored by the results. It didn't seem possible what we were seeing on the machine. And obviously, we ran a few more times and just consistently seeing millions of nanograms, a detection of millions when the FDA maximum permissible exposure to NDMA is 96. And again, there's no safe level of this kind of care center and the ideal level is zero. And we were seeing millions. And that's how this all started. At some point, I'm sure it crosses your mind. There's a mistake here. It's one thing if the FDA limit is 96. You're consistently seeing

100 to 110. But you're seeing five logarithms higher than an FDA limit. What's yourself audit on that? Gut reaction right away being a scientist is that something went wrong. Something got in there or who knows? Control went wrong, perhaps, and contaminated the column. The machines themselves were talking about, don't get data wrong.

I mean, these are forensic level machines. The machine specifically is called a GCMS, a gas chromatography mass spectrometer. It's been the gold standard for this kind of impurity analysis for decades, over 50 years. And so, you know, you start looking for potentially human error or anything else. And I went to our chief scientific officer who brought this obviously straight to my desk. Let's look through this system, let's clean it, let's run it again, let's run more controls and we kept rerunning it and rerunning it and seeing the same thing. It was very odd but the other thing that we did at the same time was starting to look at the literature.

I mean this is such an extreme finding. Five logarithms higher, five orders of magnitude higher than what is even still not a good place to be. We started reading about this, and there's been literature about it for 37 years. So you're talking about it being out at least 20, that molecule was approved in 1981. The first studies that came out that started raising concerns about NDMA and Renididine were published in 1982. It wasn't approved in the United States till 1983. And there was literally decades of studies about the instability of the Renididine molecule. There's 17 years of research in the United States over the potential of

Renidine getting into the water supply and then forming NDMA in drinking water, and they showed all sorts of instabilities in the molecule, reactions with chlorine, with ozone, with all these components that happen in a wastewater treatment plants, which are pretty much benign for anything else. which are pretty much benign for anything else. And that's when we also kind of came to the conclusion, well actually, if it's such an amazingly unstable molecule, perhaps it's just even breaking down in the machinery that's meant to test these kinds of medications. So does this mean that you were more leaning to the idea that this was not an issue specific to a particular drug,

meaning to a particular manufacturer, but rather to the drug? So when you looked at the first sample where you see a million nanograms per dose, did I hear you correctly? A million nanograms in a dose? We were actually seeing between two and three million. Okay, I'm guessing the first call you make once you decide this isn't a human error is somebody go and get me branded Zantak. You got to think that this is a contaminant from the shady manufacturer of this generic. You got it exactly correct. At the same time as we're delving into the literature, we said, okay, this is very odd about whatever was in

this particular bottle. But let's just go to all of the local pharmacies around us and by exactly the brand Xantac, which is by all the various pharmacy versions of Reniditing and Testimall, and get the cool mint version and the standard version and the maximum strength, and every single pill of every single manufacturer, label, or wherever it was coming from, including the reference powder. So, not only did we check every single bottle that we could get our hands on at the time, we also bought the certified reference powder that's as pure as you possibly can get it to rule out inactive ingredients or any interactions there. And even in the reference

powder, we are seeing millions of nanograms of NDMA being detected by this test. Well, that's, I mean, that's, that's problematic. I mean, that suggests that, let me, rather than tell you what I think it suggests, what's your Occam's razor explanation for at that moment, meaning before you do another assay, what your Occam's Razor explanation for at that moment? Meaning, before you do another assay, what does Occam's Razor suggest is happening when branded generics alike are containing millions of nanograms of something that should be completely absent? I love Occam's Razor and Occam's Razor specifically said it's a problem with the drug. Everybody's head has always been in this Valsartan and contamination and bad generics overseas

and these kinds of things which are a problem too, but this was a problem must be at just at a totally different level. As in the drug itself is just so incredibly unstable and not just unstable in terms of, okay, maybe you're going to get a less potent pill, it's directly forming NDMA, the extremely potent carcinogen, and actually one of the reasons that the specific data around these millions of nanograms was so important, regardless of the conditions, and that's now becoming one of the discussion points, is that there's no other way to get millions of nanograms, which is milligrams. I mean, these pills are at 75 milligrams, 150 milligrams. So we're seeing milligrams of this carcinogen NDMA, there's no other way that it could be there except if the molecule itself was reacting with itself

and forming it. There's no other source of nitrogen for this carcinogen of a very basic organic chemistry. I want to double click on that for the listener who might be misunderstanding what you're saying. This is such an important point that I'm a little floored. So a standard dose of renitidine is 75 milligrams to 150 milligrams, correct? Correct. Okay. So, and again, just to state this for the record, when you test a collet 150 milligrams tablet of Renitidine, you could discover, call it 1.5 million nanograms of NDMA.

Yes? At least. Right. Which I didn't write it down, but I think that 1.5 million nanograms is 1.5 milligrams, right? Correct. Okay. So that means 1%, 1% full percent of the supposedly active drug you're getting is a potential

carcinogen. And by the way, I want to come back to understanding the carcinogenic nature of NDMA but let's park that for a moment. What you're saying is just at a mass balance level, the only way you could get enough organic building block, inclusive of nitrogen to make NDMA is if you're taking some of it from the Renitidine meaning it has to be at almost decay or chemical reaction of the drug itself. Is that correct? Exactly.

Exactly. And from a chemistry perspective, that's extremely concerning. And I'll say one thing also that makes it actually 10 times worse is that the NDMA molecule is a lot smaller or lighter than the Renitidine molecule. So the molar conversion or the conversion of a Renitidine molecule into an NDMA molecule is actually even more efficient than that 1%. The numbers are suggesting 10% or so conversion of the Renitidine molecule into NDMA in an incredibly short period of time.

So what we're talking about in terms of this GCMS analysis is the way that it pretty much works is you have this vial where we have a pill in it and some solvent. And then it goes into an oven, chromatography oven, where it's being heated up and then you sample the gas and run it through a column and then run it through a mass spec. Long story short, you need to heat it up for a little bit to capture as many molecules as you can that's coming off, and NDMA is a very volatile molecule that goes into the gas. It's 15 minutes, so it spends 15 minutes at 130 degrees Celsius, which is benign for practically any other drug that we're looking at and is part of the FDA standard protocol.

And for just these 15 minutes, which in the chemistry world, there's very rarely do you have such a short reaction. Yeah, that's like cooking a scrambled egg or cooking a fried egg in 10 minutes. That's pretty low temp. Exactly. And usually if you're doing serious chemistry and a chemistry lab, you leave it for hours or days and sometimes it requires weeks. But 15 minutes of exposure and you're getting around a 10% conversion into NDMA, that's incredible instability. And again, the reason you're saying 10% for the listener is even though it's 1% by mass on a molar basis, the way we actually count molecules, it's much greater. Correct.

Let's pause for a moment and talk about NDMA. I certainly have a lot of questions about this. You've already stated the formal name of the molecule. How big a molecule is it? It's just a few atoms, right? It's a couple nitrogens and carbon and I don't have the molecular weight in front of me, but it's pretty small.

It's a tiny little thing. Yeah, NDMA is catarized as a small molecule. It's particularly small, even among small molecules. What is the mechanism by which it causes cancer in animal models? Yeah, so NDMA basically sticks to DNA. It sticks to DNA, it modifies it, it's what calls alcalates it, it also oxidizes it.

Long story short, it's very bad for your DNA and by modifying the DNA is what causes cancers. Yeah, so sticking to DNA is not the worst thing in the world. I mean, methyl groups stick to DNA all the time and that's called epigenetic modification, which can be quite bad, but can also be completely inert, and in some cases can be good.

But this isn't just sticking to it. It's changing the structure in the DNA in such a way that, well, presumably if it's a carcinogen, the definition is it changes the DNA in a way that the DNA in that cell no longer responds to appropriate cell cycle signaling. So now you have growth of a cell that can be unregulated as opposed to regulated. How well is that documented? And in what model systems is that documented? Both cell type and in vivo versus in vitro. So the background in NDA may goes to at least the 1950s. I'll say that it's extremely well documented in the 1950s. I'll say that it's extremely well documented in almost every clinical model, obviously other than human. In mice, rats, cell assays, it's been heavily, heavily studied for

decades. And like I was saying before, and it just studied, but also used actively as a control for inducing cancer in mice and rats. Just to explain to the listener, in vitro means it causes cancer in a petri dish where you take the cells out. And if something does that, that's interesting. But it's a lot more interesting if it can cause cancer inside the animal itself. And that's called in vivo. And that's what you just said.

Do you have a sense of what doses are necessary to induce cancer in rats? So this part is also well studied. I don't know the exact dose, but what I can say is that the calculus that the FDA has actually already gone through in terms of its potential effect on humans is based on these exact kinds of animal models and studies. So during all the Valsart and Low-Sart and issues, one of the statements that came from the FDA was that, well, if somebody had been taking the worst case scenario of what they'd found, which I believe was somewhere around the 17,000 nanograms or so of NDMA, taking it consistently for years, there would be one additional cancer case in

8,000, which may sound like a low number, but when you multiply that by the millions of people taking it, it's still thousands of cancer cases that shouldn't have been. Obviously, there should be zero cancer cases that come from carcinogens in your medications, and if you ask me, I'd say that number is concerning period to have thousands of cancer cases. So those animal models are actually used to at least make a best guess on what would happen in a human. And again, this is also best guess.

It could be worse or could be better. It's obviously not something you can test and to actually put inside humans. But that doesn't seem nearly as high as some of the other carcinogens that we would expect. I mean, there are other carcinogens that are used in laboratory testing that are guaranteed to cause cancer. Is the difference, you think, the dose that in the animal studies when such agents are used, they are used at astronomical doses,

but not the same here. I mean, I'm gonna tell you where I'm going with my question in a moment so that you can think about it as you answer this question, which is when you look at the ubiquity of Zantac use, the question is going to be where are the body bags associated with Zantac?

So before we answer that question, let's try to tease this idea out a bit more if you don't mind. Sure, definitely when you'd be doing a study with mice or rats and you're trying to get them to have cancer, the dosage that those animals are getting is going to be much higher than these trace amounts that are being found in the medications like Balsartin. I don't know exactly what those dosages are, but I could imagine they're in the milligrams.

Interesting. So let's now talk about this epidemiologic question. I'm not a big fan of epidemiology in general. I've sort of railed on epidemiology when it comes to nutrition, exercise, so many things, which is not to say I think it is of no value, but I think one has to be very careful, especially when you see sort of weak hazard ratios and try to infer causality. So when you see a hazard ratio of 1.17, meaning there's a 17% increase in relative risk when exposed to X. Next can be something you eat or something else. I generally have a hard time with those things. And if that is a statistically significant hazard ratio, it will have a confidence interval that is well north of one. So like the 95 confidence interval will not include the number one. That's how we sort of statistically get that.

But I find epidemiology can be especially helpful when it's not there. In other words, when epidemiology says there's no association between X and Y, it becomes a lot easier to say there's much less likelihood that there's a causal relationship between X and Y. So again, when you consider the ubiquity in size, 15 million prescriptions a year, plus I would say easily three times that in over the counter use. So let's just call it 60 million dispensed Xantex over the counter for almost 40 years. If NDMA is problematic, there should be a good collection of body bags, shouldn't there? Definitely possible. And when we were putting the FDA citizen petition together that we filed, we tried hard to look up. There are these epidemiological studies. And we found one from 2004, published by the National Cancer Institute where they looked at the

antacids at the time, the prescription antacids at the time when the study started in 1986, I believe, and they found a link to bladder cancer when looking at those antacids, which were both renitating and submitted at the time. And so it's kind of a, as far as epidemiology goes, obviously you want to look at the individual drugs not have them lumped together, but that was particularly concerning for us thinking about another study that was done by Stanford University and published in 2016,

which was the only clinical study that we could find where somebody actually gave people a pill of Xantac and they found over 40,000 nanograms of NDMA in their urine. So we may want to talk more about that in a second, but to answer your question about epidemiology, is essentially, it was just so assumed that this is such an incredibly safe drug that at least as far as we could find

that there just wasn't much of that study out there. However, we have been working with a number of folks at Memorial Sloan Kettering Cancer Center, and there's been for at least a few months now a lot of efforts led by Leore Bronstein to look into exactly that question. I mean, obviously, as you know, to do a full breadth epidemiological study, I mean these can take years, but we are looking forward to hopefully get the initial results from Leore Bronstein and his team as soon as we can get him published in the journal. And so what it really suggests is if there is an increase in the risk of human cancers from the use of this, it's not going to be alas smoking.

I mean, it's important, I think, for people to understand the magnitude of risk here. In the case of cigarettes and lung cancer, the hazard ratios, depending on the epidemiologic studies that were done, I think they varied somewhere between 8x and 14x. And I could be off by a little bit, but I'm not off by much. So what that means is if you smoke, if you reach a certain dose threshold of cancers, your risk of lung cancer is somewhere between 800 and 1400 times higher than a non-smoker. And the words of one of my good friends

who's almost assuredly paraphrasing someone else, when you don't need statistics to see the answer, that's usually a scary thing. And that was certainly one of the cases. You didn't need complicated statistical models to tease out the relationship between tobacco and lung cancer. Now that does not mean because Zantak obviously doesn't fit that. I mean, I just can't imagine we wouldn't see some signal, but it could have a hazard ratio of two.

Meaning it could double your risk of a cancer, and because it's so ubiquitous, and if it's doubling a cancer that is itself ubiquitous, that's the fear. Let me explain why to the listener, because obviously you would get this, David. The reason that lung cancer was easy to spot from smoking is lung cancer, absent smoking is quite rare. So epidemiology is that it's finest when the signal is huge and the thing you're studying is unusual.

And that's why I believe epidemiology is almost as useful as a warm bucket of hamster vomit when it comes to studying nutrition. Because when we study nutrition, we're interested in the diseases of civilization, diabetes, obesity, and things like that. But the problem is those things are so ubiquitous. I mean, there are so much of those things

that it's very difficult to pick up signals associated with lifestyle factors. So I guess what I'm trying to get at them and feel free to disagree with me. I'd like for you to disagree or refine my thinking, but I'm trying to make sense of this on two levels. One, how big a problem is this? And two, what are our blind spots? I think you're basically saying we don't know how big a problem this is, and that's the fair answer because the study hasn't been done. We haven't looked at the cases and the controls, meaning the people who have taken it and the people who haven't.

But the magnitude problem and the blind spot problem really come down to, we will not know the answer until we figure out which type of cancers. Because if it increases the risk of a very rare cancer, I suspect that would have shown up. I just think if there is a huge uptick from 1980 until today of some very rare cancer, that would be a lot easier to point to an environmental contaminant such as a drug. But if it's increasing the risk of breast cancer and prostate cancer, which are large cancers to begin with, it would be harder. Do you agree with my assessment?

I know you're not an epidemiologist, but you're a clever guy and you've thought a lot about this and you thought about it more than I have. Well, I think it's going to be a very interesting conversation to get back to when the results are published. And I will say that the big problem, I think, that's certainly underscored with this monitidine issue is that just nobody was looking. You could argue that how would they have known where to look, which I can also point towards lots of studies and information should have been looking at NDMA, but nobody was obviously looking for the NDMA before, and nobody's been looking at the epidemiology before. There have been a number of rare cancers that have gone up that have been unexplained. Some of them starting in the 1980s.

So let's defer that question for when there's more data, of course. And I think this is something that is going to take years to really get down to what is the total impact for real. But I can't imagine it's going to be zero. And anything greater than zero multiplied by the millions of people taking it for 40 years nearly is a tragedy. Especially when you consider that there are no shortage of substitutes that are equally efficacious if not better.

I mean, that, I think, comes down to. It's one thing if this were the only drug out there that could treat patients with HIV, in which case you have to weigh out the benefits of a drug versus the costs. But when we're talking about reducing gastric acid, which again, there are more drugs in that category than I can certainly count, it begs the question why. Now, I want to go back to something you said. So you brought up the study by Zang in Mitch in 2016 at Stanford. I never heard of that study until I started looking into this Zantac Renididine story. Presumably, you hadn't either until you made your discovery and went back. Why did the

Zang in Mitch's article not get more attention given the largely accepted carcinogenic nature of NDMA and the, I mean, staggering nature of the study. If I recall the study, one pill, 150 milligrams, given to subjects overnight who had been not taking it before, and you just collected the urine, and you found, I don't know, was it 40,000 nanograms of NDMA? Right. Over 40,000 nanograms in urine, which, in and of itself itself sounds really bad, and

obviously it is, but it's actually at least a hundred times worse because the renal clearance of NDMA, so how much NDMA actually makes it into the urine, is that often 1% or less. And that's because NDMA sticks to DNA and your body is full of DNA and it's reacting all over your body. And so very little bit is actually expected to make it to the urine. So really what those results were suggesting is that somewhere around 4 million or millions of nanograms of NDMA are being exposed in your body with a single pill of Xantac, and they were using the Xantac in that particular study, which, again, loops back into our results that we were seeing in the lab conditions, also the potential of this molecule to 4

millions of nanograms. So totally agree with you, it was an extremely eye-opening study. And to go back to when we had Valisher were originally finding this problem, and Cory Kachera, our chief scientific officer, brought it to my desk, and we started looking at the literature. That was, we were not aware of that study beforehand, but as soon as we saw that study, we were like, what? Like this is, this is an extremely alarming study. Yeah, and it sort of validates your numbers because if one pill is putting 40,000 in the urine, as you said, you could assume that there was four million in the bloodstream, that's the same order of magnitude as what you found in your chemical analysis, which may or may not be compromised by temperature, which we'll come back to.

So why didn't that study get more attention? Is my question. I mean, honestly, Professor Bill Mitch, great guy that is in the environmental sciences. So he'd been looking at this Renididine problem himself at Yale University, at Stanford University, for 17 years. His first papers published in 2002 were concerned about where does NDAA come from when it's in drinking water and coming out of wastewater treatment plants. The irony of how this all came up for him was actually that there's this big environmental problem where they had this rocket fuel plant where NDAA is often a byproduct of rocket fuel manufacturer.

They were dumping into a river and all of a sudden there is all this NDMA drinking water and a lot of attention to NDMA, a very well-known carcinogen. What they found is that even after they cleaned it up and even after they started looking in other cities, they were still finding low levels of NDMA. Basically, sparked the 17 years of research for Bill Mitch, and all the various folks that he's been working with, and in this field of environmental science of water quality. And I think this has been like this big red button,

serious problem in a more obscure science than the medical community is used to. I'm sure yourself as a doctor, try to keep up with a variety of journals or scientific findings, but I don't know how often you're looking up environmental journals. I can tell you the answer to that.

It would be never. Right. Right. And look, I think what we found ourselves in the position at Valeshire was adding some new science and some new discoveries that we found, but really we were just connecting the dots over 37 years of research.

And what was very clear also in Mitch's paper of that specific study was that there was some sort of missing biological link, because there's also been a lot of work, which we also recreated, which Bill Mitch did as well, looking at the stomach, just conditions of the human stomach, and you tend to find hundreds of thousands of nanograms of NDMA, which is also very bad,

being formed by the Reninidine molecule. But his study was pointing to the possibility of millions, and therefore, Reninidine forming even outside of the stomach, and the body being extremely complex, which drove us at Balscher to look more toward, well, is there a potential biological link here as well? And we identified an enzyme, a specifically DDAH1, but this enzyme has also been well characterized

for many years. And what it does is it just grabs on to a molecule and it breaks off this DMA group. So NDMA is the N and the DMA components. And once you break off a DMA, it's very easy to form the NDMA. There's nitrite that fully circles in your body and lots of other ways to make it.

And so essentially we looked at this enzyme and did computational modeling to find that seems that the runidity molecule fits extremely snugly in this enzyme. And that at least gives a potential biological mechanism for forming millions of nanograms throughout the body, even outside of the stomach. We essentially had now that biological link and the chemistry side and then all the way into the full body clinical study that Bill Mitch did that makes a very compelling story that Renidium is just a toxic molecule in the human body.

So let's talk about the FDA's response to all of this. What was the first date you made public your findings? So we actually confidentially alerted the FDA back in June. I don't recall the exact date. We filed an FDA citizen petition that made our much deeper analysis with the biological link and everything else that we were studying. We filed that September 13th. But we did, even without having the full story yet,

we thought the results were so alarming that we did this kind of confidential filing to the FDA. We didn't want to be publicly talking about these kinds of problems if we didn't have the full story. Obviously, Cognizant that this drug industry can be extremely litigious. A lot of lawyers don't like it if you're talking about a particular drug badly. So that's when we did the initial alert and continued to analyze this. And then obviously the FDA made their own announcement, also September 13th. So the September 13th date you filed the citizen's petition was the date that the FDA said that trace amounts. Well, actually, I don't have their statement, but do you know exactly what they said? I mean, I remember reading it because at that level, it starts to even get

it. Even guys like me will start to see it when the FDA is saying it. But how did they word their response to the citizen's petition? So the FDA's statement Friday the 13th, September the 13th was, I don't have the exact wording in front of me, but that they had found an impurity and DMA

at low levels. I think they made some references to barely exceeding those that's in food. Kind of feels like no big deal, but they're still making an alert and wanted everybody to be aware of that. And us, we've been working for months now on this issue and putting together this citizen petition that has all the information that we've studied about the chemistry, the biology side of the components, a bunch of citations, as much as we could find in terms of complete document. And we were actually quite taken back by the fact that the FDA made this kind of announcement

on September 13th. And although the citizen petition wasn't complete yet with epidemiological results, we felt that it was very important to publish it, get it on file, and have everybody see the full story that includes these very alarming findings on the chemistry and biology and underscoring Bill Mitch's study, which all these things, even just by themselves, are so

incredibly concerning, that even though we didn't have the epidemiology done yet, we definitely felt should be published. Now, the FDA has the authority to do a lot. I certainly learned what they don't have the authority to do in talking with Catherine Aban, but Did they have the authority on September since that was a Friday? Let's give them the weekend to think about it But on September 16th that Monday did they have the authority to pull all forms of Renitating and Zantec off the market in the United States. I believe they do They definitely the very least, have the authority

to request manufacturers recall it. When you hear about recalls, it's almost always voluntary recalls, but FDA can push for it. Interesting that you mentioned that the following Monday or Tuesday of that week, that's when the first other health system, Canada, so health Canada made a statement September 17th that Tuesday with a very strong message

of requesting all companies to stop distributing all forms of Bernadine. And the second line in that statement was current evidence suggests that NDMA may be present in Bernadine, regardless of the manufacturer, which directly underscores what we were finding that it doesn't matter how it was made or where it was made, just

that the drug itself is so incredibly fundamentally unstable that it can directly form NDMA in a whole variety of conditions and should just be taken off the market. Yeah, well, I'm Canadian. I'll take a little victory lap on the conservative nature of health Canada, totally kidding. How many countries besides the great nation to the north of us have followed suit with Canada? So, to date, now we're still just only a few weeks away from this September 13th announcement.

Roughly 30 countries have recalled or banned Reneidine and not just places like Italy and France and Germany, but you have Kenya, Libya, Bangladesh, Saudi Arabia, Pakistan. Pakistan actually came out not just recalling all Reneidine products, they actually told all the manufacturers in their country to stop making it. As in, stop everything you're doing with anything related to renidating. Stop it. And that was in Pakistan. I mean, I just don't even know how to make sense of this, David, to be completely honest with you. So I sort of get Canada's reaction because they were the first to react and they reacted before the FDA had done what they've

done over the past few weeks. Do you think a lot of these other countries are just in a herd mentality motor? Do you think they've independently taken a look at your data, your petition, and come to the same conclusion? I know that's an odd question, but the real question I'm getting at is why has the FDA resisted taking stronger action? Each country has, obviously, their own health systems. I think a lot of these health systems have certainly looked towards the FDA, but we were contacted by a number of press

that we're also talking with, the health agencies in their countries. We talked extensively to folks in Switzerland, in Germany, in Poland, in India, in Russia, and it seemed that quite a few agencies were running their own tests. We know specifically in South Korea, they even published some of those results. They were finding at minimum 2800 nanograms of NDA and their worst was 32,000 nanograms of NDA that was found by South Korea's regulators.

And these numbers in of themselves are obviously not good, but I think one of the unfortunate things that happened out of the FDA's original statement is that it made this whole thing just sound like a contamination. And I think you saw this a lot with countries too, is that some of them like Canada, I think realized early on, perhaps seeing our petition or just looking at some of the data like Bill Mitch's study, that this is an inherent problem with the drug. And therefore, stop all manufacturers, stop all distribution, whereas some other countries were banning certain manufacturers that maybe they tested or they had some data suggesting

that this manufacturer had some level of contamination in it of NDMA. But even that contamination may will talk more about this of contamination versus inherent instability. There's actually a great article in India that talked about this of why has France and Germany banned this substance versus the time India and the United States had not and a lot of what they were concluding is that some people are looking at this as a contamination that maybe happens here and there and some are realizing that the reality that unity is a fundamentally unstable molecule and concernedly caused contamination as a byproduct of being unstable but has a seemingly very high risk of forming tremendous amount of endumane.

The human body and she just be taken out completely off the market. So the FDA released a statement in early October that basically said to the effect, hey, we're going to continue to test Renitityine in its products. We're not saying there's nothing wrong here, but they did very specifically challenge your method for testing. And they said specifically, and this I do quote, it is not suitable for testing Renitidine because heating the sample itself generates NDMA and presumably they mean heating it to the low temperature of 130 degrees Celsius. Right. So yeah, that exact quote, heating the sample generates NDMA. I mean, they don't mention that specifically, but they do say third-party laboratory, which ironically in the press, I don't

think they even bothered talking about that. They just inserted the name valesure. But I think at the very least, nicely underscores that even just some heat, which again is benign for practically all these other molecules, is enough to generate NDMA. So yes, exactly, we agree heat that could be happening anywhere in transit, could be in a hot car or anywhere else, could directly degrade this molecule, not just

into falling apart, but into falling apart directly into NDMA. So how do we get to the root of this problem? Because this could end up being the jugular issue. I mean, in many ways, the Zang in Mitch study suggests you don't need heat. Has the FDA commented specifically on that study? Not that I'm aware of. There's plenty of studies out there that look at all sorts of other conditions that degrade reniditing. Like, they're not even looking at, in general, they're just saying, okay, here's reniditing and let's see what happens when we add ozone that is commonly emitted by all sorts of devices and things, or chlorine that you use for cleaning all sorts of things, and also is used in wastewater

treatment plants. And even the reaction mechanisms were specifically ironed out chemically of how renidine degrades directly into NDMA with these relatively minor and benign conditions. And certainly, the condition that concerned us at Valsher the most was the conditions of the human body. So, yes, we in the introductory paragraph in our citizen's and petition also comment on how the FDA method that we use, that was the method available at the time for the analysis of NDMA, we suspect that this 15 minutes of 130 degrees temperature is causing an incredibly efficient reaction of generating NDMA from renititing. And so therefore, we modified that particular protocol,

and I should also say that the vowsher, apart from having some great scientists that work with us, we are an ISO accredited facility specifically for the analysis of NDMA. So we modified the protocol, did the proper controls, and put down the temperature. So we developed another method still using the GCMS and essentially copying the rest of the FDA protocol,

and then bringing down the temperature to body temperature. And in this specific way of analysis, we didn't find NDMA in the tablets that we were looking at. And so we used this low temperature version to analyze conditions of the human stomach. Actually very similar, almost exactly the same conditions that Bill Mitch was using in his study, and others have used it in other studies before, where essentially we have simulated gastric fluid and nitrite present, which seems to be particularly capable of reacting with rinidadine in your stomach, and is just present

in a lot of foods in general and in the human body, even without those foods. So we created those conditions, put one pill of Xantech into essentially 100 milliliters of this kind of stomach fluid, and then using the low temperature system, analyzed that and found very similar numbers as Bill Mitch was finding is in the hundreds of thousands of nanograms of NDMA. So we found up to 300,000 nanograms. Bill Mitch's study found up to 400,000 nanograms. So pretty similar results, a very high formation of NDMA in a body-relevant condition. So David, let me just make sure I understand that. So obviously the GCMS gold standard,

you can't get around it, you have to be at 130 degrees Celsius in the oven to incubate it. That's going to produce the numbers we've discussed. But you're saying you came up with a different test, which is instead of just taking the pill, crushing it, sticking it into the GCMS, you dump it into a 37 degree Celsius bath that is modeled after gastric secretion. So it'll have a pH of two and it'll have this and that other co-factor and enzyme. And you're saying when you took that little soupy bath, you did not have to put it into the GCMS or you did, but you just ran at that 37 Celsius instead of 130. I wanna make sure I understand how you can do

a low temp assessment. Yeah, important question. That's somewhat of the annoying part of where this discussion is now gotten to with these statements is now the devil's in the details. So, okay, what you described is how we prepared the sample, so the kind of this bath that's emulating stomach conditions, and to analyze that bath, we had to put it still in a GCMS, but now a low temperature profile of the GCMS, which what that does when you lower the temperature in a GCMS is you've gotten less sensitivity. So instead of being sensitive down to 25 nanograms, which is what

the FDA protocol gets and that they publish, and what we were getting in terms of the sensitivity when you as 130 degrees, when you take it down to body temperature, now you're at 100 nanograms of sensitivity. So a little bit less sensitive. So obviously, if you're trying to be a good chemist, you would put it up to 130 degrees and get the highest possible sensitivity, which I'm sure is why the FDA published that protocol at 130 degrees.

And again, it's fine for Valsarden and almost every other molecule that we've ever looked at. Why is that the case? Why was it fine to go to 130 degrees Celsius with Valsartin? Valsartin is not unstable. In other words, the NDMA in Valsartin is thought to be a contaminant and not a product of degradation. Exactly. Okay. So can you run the GCMS at 37 Celsius? And is that what you're saying you can, but you can only dissect down to 100 nanograms? Correct. Exactly. So this is splitting hairs here, but who cares when you're dealing with a concentration as high as you're dealing with, right? Exactly. And who cares when there's already a clinical study that was done. We can argue all day about the conditions of the stomach,

of various things, you can never recreate biology, right? As soon as we're talking about biology instead of pure chemistry, which is when the data of using the FDA protocol and seeing milligrams of NDMA form from reference powder of Rennidine, that's chemistry analysis. So our conclusion from that is that rinidine is incredibly unstable, conforming milligrams of NDMA in 15 minutes, and there's no other

way you could have done this except from the source of the drug itself. As soon as we start talking about biology and stomach conditions, really the ultimate test there is a clinical test where you go through the entire human body, which is exactly what Bill Mitch did at Stanford University. Although did he use 130 degrees Celsius on the GCMS on the urine? Because the real gold standard might be, or I wouldn't say the real gold standard, another elegant test would be you take a person, you give them renitating, you collect the urine, and without doing anything, you run that urine at 37 Celsius.

And if that showed what Mitchell found, or even close to it, if Mitchell found 40,000, let's just say you found 4,000. Let's just say that the difference between 37 Celsius and 130 Celsius on the breakdown product, because again, the question, we don't know is, is this person peeing out some byproduct of renitidine that then further decays to NDMA, or they just peeing out straight NDMA? And if they are, then the temperature should make very little difference in how much you detect,

correct? Right. Actually, when we saw Bill Mitch's study and also seeing what we were seeing in the GCMS, we called Bill and started asking him about his work and everything else. We were pushing on some of those questions as well. He wasn't using the FDA method, but obviously the devil is in the detail of all these methods.

And he went back and did some significant controls to validate these kinds of systems, was something being created in the instrumentation. And after all of his validation, he was still seeing over these 40,000 nanograms of NDMA. So how confident are you, and again, the answer can't be 100% or you wouldn't be a scientist, which I know you're a scientist.

So how confident are you that grossly elevated levels of NDMA are being made from Renididine that is not at all an artifact of instrumentation, human error, or most importantly, temperature contamination? Extremely confident. And you hit it on the head that as a proper scientist I can never be 100% on anything of course but the data is just overwhelming and the other part of this is as you've mentioned before you know this isn't some life saving drug that there is no alternatives for where we say you know what we're 99% sure but there's 1% that

maybe we're a little bit off here and people depend on this for their lives and let's think about that versus the fact that they may cause some cancer over time. It's not the case. Plenty of alternatives, as you've mentioned. This is not a life-saving drug, so I don't see how any of that calculus plays into thinking that this should just be taking off the market.

Yeah, and I would add another layer to that, which I guess is why I wanted to speak with you about this is I have a little bit of a background in risk, in a formal training in risk. In risk training, one of the things you're always taught to look for is asymmetry of risk. So if you have a bet, if you bet somebody $10 on the outcome of something, so you put $10 in, they put $10 in. That's not a very asymmetric bet. You're going to win $10 and therefore walk away with 20 or you're going to lose $10 and lose your money. Those are great bets to make because you have a sense of what the downside is and what the upside

is. But what I really struggle with here, David, is this is a very asymmetric bet that the FDA is making. There's a chance you're wrong. There's a chance that in a few years, all of the data will be in, including what I consider arguably the most important data, which will be the human epidemiologic data that tracks the cases and the cohorts. And it will show that Zantek is totally fine, and further chemical analysis will reveal that there is some error in the methodology that you and countless others have made. It doesn't sound like that's the case, but it could be. In that case, the FDA will have been the hero for not recalling the drug.

What's the upside in that situation? Conversely, in five years, if the epidemiology or two years or whatever, suggests the opposite, which is this totally unnecessary ubiquitous drug increased by two and a half-fold a risk of cancer, a fill-in-the-blank cancer, and when the FDA was notified of this, they did nothing. That's a very asymmetric downside. That downside is infinitely greater than the upside of having done nothing. If anybody at the FDA is listening, I'm sorry if I sound like I'm being a jerk, but I can't

help but ask, what is your chief risk officer telling you right now? Because if I was your chief risk officer, and I didn't know a thing about biology, I'd be explaining this to you. Where is that discussion, David? Do you know enough about the FDA to understand that? Do they have a chief risk officer? We have had no interaction with the FDA, we're throughout all this other than our submitting of the citizen

petition and seeing what they're saying about us in these statements. Huh. Well, I guess the only thing I can tell you is here's what we've done. We've told that we have three patients in our practice that takes antics, so the first thing we did, when I really figured out how serious this was, which was not on Friday the 13th, by the way, the front of the 13th, I took the FDA's word for it, stupid Peter, sorry. But it was a few days later that a little bit more digging made me realize, the FDA might

be making a mistake here that we went and scrubbed the medical reconsiliations of all our patients, realized three of them took Renitidine, luckily none of them regularly. We just called them immediately, said, stop taking this drug, do not pass go, do not collect $200. Here's the drug you're going to take instead. Presumably anybody listening to this, I'd feel pretty comfortable suggesting they do the same. What else is there to do? What can citizens do beyond not taking this drug themselves and passing along that insight? Is there anything that the citizens can do with respect to the FDA? I mean, how many citizens petitions does the FDA get a year, by the way?

I'm not sure what that exact number is. It's used for such a variety of different things, but I think they get a few of them a week. Yeah, but I assume that they're all different, right? I mean, obviously they're all different. I guess what I'm saying is I assume they're of different magnitude of importance. I mean, when a chemical lab of yours stature is submitting this type of data, that's probably different than if I just rung up the FDA and said, hey guys, I noticed when my patient took crestor at work, and when he took Resuvistat

and it didn't, that's the type of citizen's petition I assume that doesn't go too far. But do you have a sense of how many citizens' petitions of your nature and gravity hit their desk? I don't think very many. Do you know how the FDA set the limit at 96 nanograms, by the way? Yeah, so the calculus behind that is basically ensuring that there is less than one cancer case in 100,000 over the course of 70 years. That's an extrapolation from an animal model, correct? Correct.

So again, as a scientist, it could be, maybe it's not that bad or it could be worse. Humans are not the same as a mouse. Well, David, is there anything else you want to say on this story? I mean, this is, I got to be brutally honest with you. I was a little bit reluctant to speak with you so early in the development of this story because I know that time always brings new insights. But at the same time, I think truthfully I felt a little bit a sense of responsibility. Feel fortunate that we have an audience now that is quite large, and if for no other reason, then if this message gets to a lot of people who then share it with a lot of people,

it can make a difference in at least some people's lives. And again, my calculation is on the asymmetric side of this, if this is wrong, I still feel like we've done no harm in that, at least to a person, meaning, we've harmed a company. Let's be clear, if this is wrong, all the companies that make, who makes Xantec, by the way, is it Sinofie? Sinofie, the rights to the United States,

it's made by a whole bunch of different companies. Right, right, so you've got all the generics and Sinofie that makes the brand it,, etc. I mean, let's be honest. Let's look at it from their standpoint. They're being hurt by this. And if this turns out to be wrong, that's potentially devastating financially. I guess I am taking a slightly different risk, which is that the risk of someone switching over to a different H2 blocker or proton pump inhibitor is the

worst thing that's going to happen. And the best thing that happens is hopefully some cases of cancer could be averted over the next, God knows how long. That might be naive, but that's sort of the reason I wanted to talk with you, but I'm uneasy of the fact that we, there's more questions than answers to one other thing, actually, that I think is important to underscore here and could also play into this overall upside down side calculus is that the reason this whole issue came up again in the scientific literature in the early 2000s is concern over water quality, an NDMA in drinking water. And what we mentioned in the petition that is getting very little attention, unfortunately, is that

now that there's all this news and everybody is worried about it for one reason or another, or whatever the reading about Xantec and Renidine, if you're throwing it away in the sink down the toilet, even in trash, which goes to landfills and bleachate runoff from that can be treated in chemical methods. All of this is exactly what all these environmental scientists for the last 17 years have been saying is a potential problem because it will form NDMA in the wastewater treatment plant, which then gets used as drinking water. So we certainly feel that if you're making the decision to no longer use a renidine product, make sure you don't just throw it away. Or certainly don't

throw it down the sink or down the toilet. It needs to be disposed of properly. I mean, essentially, it's got to be disposed of as toxic waste. It's got to be returned to the pharmacy or to all these facilities that do medication disposal. Because another potential downside of all of this is that everybody's dumping it and it's going into the water system and then being converted to high levels of NDMA in drinking water and now you have another potential crisis. Well, that's a really good point. So again, just to make sure the listener understands exactly what you're talking about, it's one thing to say, wow, this is an issue. I'm going

to stop taking my renitidine, but to flush it down the toilet or throw it in the garbage potentially spreads the problem. Now, have you heard of pharmacies accepting samples back and doing whatever is appropriate to dispose of it? I mean, from a practical standpoint, what could somebody do the day they're hearing us? I think specifically, I believe it was Walmart or some of the big pharmacy chains have said that they'll take your product back and even give you a refund. I mean, I don't want to put words in their mouth, but it's something that pharmacies are set up to do and quite sure that a number of them have gone out and said that you can even get a refund for this. Well, David, this may not be the last time we speak, because I suspect one, there'll be more do and quite sure that a number of them have gone out and said that you can even get a refund for this.

Well, David, this may not be the last time we speak because I suspect one, there'll be more to this story, but I suspect that there may be other interesting health issues that crop up as a result of your work. But again, I want to thank you for speaking on very short notice. I want to thank you for speaking with me on a Saturday night and more than all of that. Of course, I want to thank you for the public service that your company does to take care of a problem that honestly a couple of years ago, I thought was non-existent and now between your work and certainly that of Catherine's I've come to really, really doubt the veracity of the FDA and in general our regulatory environment. I don't say that lightly. I certainly think the FDA is an amazing organization and I think we're richer for it with respect to what most countries go through. I've met many people who work at the FDA. They are there's great folks there. I want to be clear that I'm not disparaging the FDA, but but there's something fundamentally wrong with this type of decision making and I don't know where the buck stops, but I'm definitely frustrated by this and I want to make sure that people are at least

armed to make their own decisions, which may differ from mine and yours, but at least they're informed. Absolutely, and I would totally echo that. There's tremendous good that comes out of the FDA and tons of great people that work there. And I certainly hope that these kinds of scenarios will at the very least bring more overall engagement on these issues. And I also not entirely sure what all the decisions are being made here. And I wish that there would be faster action on this specific

runnidity in case. But we certainly hope to work with FDA and regulators as a whole on these real problems. I think obviously we have to come to the grasp the reality that there are problems in the medication system in generics, potentially even brand, and all sorts of holes that exist in how the system is now for medications. And we want to be part of that solution and work together to ensure that every patient is getting a high quality medication. Yeah, well, thank you very much, David.

I appreciate your time and I look forward to seeing how this story unfolds. Yeah, thank you very much, Peter, as well, for spending the time on your Saturday night. You can find all of this information and more at peteratamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog at peteratia-md.com.

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