The Peter Attia Drive - #75 - David Light： Zantac recall due to cancer concerns

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00:03:58.200 My guest this week is David Light, the CEO of Valisher, which is an online pharmacy and analytical

00:04:04.300 laboratory that tests the drugs it dispenses. As some of you may have heard on September 13th of

00:04:10.460 this year, a citizen's petition was filed by David's company to the FDA requesting the immediate attention

00:04:17.140 to and potentially removal of a very common drug called Zantac or ranitidine from the market based on a lot

00:04:24.640 of analytical horsepower that they had thrown at it, suggesting that Zantac ranitidine in its generic

00:04:31.480 form was unstable and it decayed heavily into a carcinogen known as NDMA. The details of this,

00:04:42.240 obviously we discuss in the podcast, but they are quite staggering when you consider the magnitude at

00:04:48.160 which this decay occurs and therefore the level at which people could be exposed. Now, the purpose of

00:04:53.240 this episode, of course, is not to scare people, though in the end, I do something I rarely do,

00:04:58.820 which is make a recommendation, which is if you are playing this through the lens of standard risk

00:05:05.600 analysis, the better thing to do is to probably at least yourself stop taking this drug, even if the

00:05:12.100 FDA, which at the time of this recording has not asked for a withdrawal, either voluntary or otherwise.

00:05:19.660 It's important to note that at this time, 30 other countries, including Canada, many countries in

00:05:25.480 Europe, the Middle East have done that, have gone to the step of saying this drug is off the market

00:05:31.540 until we clarify what these issues are. In the first 20 minutes of this episode, we get into the

00:05:37.740 background and it is kind of important to understand David's background in chemistry and the background of

00:05:42.440 how this company became formed and what the impetus was for that. We then get into kind of their

00:05:47.220 first real insight that they made at the public health level, which was the discovery of a

00:05:53.320 carcinogen in a very commonly prescribed blood pressure medication called Valsartan. And in this

00:05:59.600 case, it was a contaminant, meaning it was not unique to the entire drug, but only to certain

00:06:04.780 manufacturers. However, the majority of this episode is devoted to the discussion of Zantac and

00:06:10.580 Ranitidine. I don't need to really say much more. I think the episode speaks for itself and it is

00:06:15.860 timely. And again, if you've never taken Zantac, don't care about this. Great. Might not be an

00:06:20.380 episode for you, but if you know anybody who takes this and at last check, 15 million prescriptions

00:06:26.480 of this were filled annually in the United States. And when you consider the over the counter being

00:06:31.520 easily two to three times, the number of that odds are, if you're listening to this, either you take

00:06:36.000 Zantac or know somebody who does at the very least, you'd want to pass that on to them. So without

00:06:41.760 further delay, please enjoy my conversation with David Light.

00:06:48.220 David, thank you so much for making time to speak on a Saturday evening.

00:06:53.320 My pleasure. Likewise.

00:06:54.880 If the listener is wondering why we're having this discussion on a Saturday evening,

00:06:58.080 it's in large part, I suspect, because this is kind of a timely issue. And so many of my podcasts

00:07:03.920 are scheduled out months in advance, but this was something I didn't really feel should be put off

00:07:09.300 for several months. So I thought if you were willing to talk on a Saturday night, then I would too.

00:07:15.420 Thanks for having me.

00:07:16.220 Yeah, yeah. So let's spend just a couple of minutes on some background before we jump into the real

00:07:22.660 meat of this discussion. I first learned about you through a woman named Catherine Eban. Do you know

00:07:30.240 Catherine?

00:07:30.940 Yes, I do.

00:07:31.820 So you may know then that I interviewed her a couple of months ago, and it was honestly for me,

00:07:38.440 one of the most upsetting interviews I've ever done. I guess I haven't interviewed enough bad

00:07:43.340 guys in my life. Not that Catherine's a bad guy, but she was really talking about a story that was

00:07:47.660 for me very disheartening, but I think also for virtually every listener kind of just blew people

00:07:52.580 away. And I knew that the moment we published that podcast, which we did in probably early

00:07:57.120 September, that there was going to be a lot of questions coming out. A lot of people were going

00:08:01.400 to wonder what the implications of this were. And even just in my own little tiny bubble of a world,

00:08:06.480 which is my very small medical practice with fewer than 100 patients, the implications have

00:08:11.260 been pretty significant. We have basically changed the way we do everything in terms of we now

00:08:16.340 exclusively work with one pharmacy. That pharmacy, while not able to do what your pharmacy does,

00:08:21.500 and we'll talk about that in a moment, they're able to do something pretty darn good, which is at

00:08:25.280 our discretion and without any hesitation, they will dispense exactly which medications we want.

00:08:30.480 So branded when the patient is willing to pay for branded, and if generic, then they are able to do

00:08:37.940 what we do with them. Actually, we do the heavy lifting, I suppose, which is we go and look at the

00:08:42.460 company that makes the specific generic and look to see if there's been any interaction with the FDA.

00:08:48.020 Now that doesn't guarantee that we're safe, but I think it's reducing our odds a lot. But let's now

00:08:53.060 talk about what you do professionally and within the pharmacy space, and maybe a little bit about how you

00:08:59.640 even decided to do that. Sure. So Valisher, a company that I co-founded and the CEO of, is an online

00:09:07.600 pharmacy, but it's also attached to an analytical laboratory. So it's actually the first pharmacy,

00:09:13.700 whether online or not, that is chemically validating samples from every single batch of every single

00:09:19.860 medication that comes through our pharmacy, and screening out those that have problems, and quite a few do.

00:09:25.760 And then for our patients, only dispensing those that pass, and we also dispense it with a certificate

00:09:31.980 of analysis, very much like nutritional information. I mean, you don't buy food without looking at the

00:09:38.420 nutrition label and seeing what's in it, but where is that for your medications? So in that certificate

00:09:44.080 of analysis, we're actually giving the information of what we've actually analyzed for that particular

00:09:49.580 batch of that particular medication. Now, a lot of people might be saying, well, David, why is that

00:09:54.340 necessary? I mean, didn't the FDA already do that? Isn't the point of having the FDA that when I go

00:10:00.320 into my pharmacy and I'm dispensed my blood pressure medicine, isn't the FDA's seal on that in the same

00:10:08.580 way that the USDA's seal is on the chicken breast that I buy at the grocery store? So the FDA's seal is

00:10:15.780 on it, but I think a lot of people are rather shocked to understand that the FDA is not doing chemical

00:10:22.020 testing on the vast majority of medications that are out there. The testing that is done sometimes

00:10:27.600 in some of the batches are done by the manufacturing companies themselves, which these days are almost

00:10:33.540 entirely overseas. Eighty percent of drug products in the United States are manufactured in either India

00:10:39.360 or China, and then self-reported to the FDA. So there's obviously a lot of options for problems and

00:10:47.620 cracks in that kind of self-reported system. These days you hear a lot about self-reporting system

00:10:52.860 problems with aviation and the Boeing 737 MAX. An airplane exploding is obviously a very visible

00:10:59.360 component of something going wrong, but your medications going wrong is actually very hard

00:11:03.940 to see or to find out. And then not to mention, as you mentioned, Catherine, even before she did a very

00:11:09.520 deep study of all the fraud that goes on when there's a self-reported mechanism. So we definitely saw

00:11:17.260 that and said, this is not acceptable for how we would want pharmacy to be. Valisher actually started

00:11:23.920 with a good friend of mine from college that called me up one day and was telling me about all these

00:11:28.060 problems he was having with his anticonvulsant medications. I mean, essentially every once in a

00:11:32.060 while he'd refill it and just have this terrible month, get all these side effects and relapses

00:11:36.880 sometimes and just felt very different from how he felt otherwise. And he talked to his doctors and

00:11:42.920 he's got some great doctors and the doctors are telling him, listen, you know, this system

00:11:45.600 is problematic. 90% of what's out there these days is generic and it can be made from all over

00:11:51.100 the place. And I think as you're kind of alluding to in terms of working with one pharmacy, just

00:11:56.080 switching from generic to generic could be problematic. They're formulated differently.

00:12:01.260 They're allowed to vary in their bioequivalents by 45% from one another. So our high level solution for

00:12:08.460 this was we want to actually have medications chemically tested at the end of the supply

00:12:14.120 chain in the United States where it matters most and test them, see what's actually inside of them

00:12:20.260 and then decide if we want to actually dispense them.

00:12:23.560 Forgive me for being skeptical because while today this sounds like a great idea,

00:12:27.700 how long has Valisher been around?

00:12:29.500 My friend Adam and I, so Adam was the one that called me up with this issue. We started

00:12:34.200 the company in 2015 and originally looking at this as a technology problem. A potential reason why

00:12:41.920 nobody's been doing this before is that the technology can be very expensive and cumbersome

00:12:47.560 and really just tailored to one or two drugs when you do this in a manufacturing plant and in pharma

00:12:52.420 companies. But if we wanted to do this in an economical way at the end of the supply chain,

00:12:57.840 there's kind of this technology gap. And so we actually spent a number of years developing

00:13:02.120 core technology, a spectroscopy based approach, essentially applying lasers to pharmaceutical

00:13:07.900 analysis so that we can do some of the most difficult and costly components of this analysis

00:13:13.900 in a much higher throughput, much easier to use way while still maintaining a high precision.

00:13:21.780 And after a couple of years of bootstrapping this whole thing and putting a lot of our

00:13:26.140 own resources into developing the technology, we achieved it. We got ISO accreditation on the

00:13:32.960 system itself. That's the International Organization for Standardization. We filed patents.

00:13:38.180 We kind of thought of this as the traditional biotech model, which is where the kind of industry

00:13:42.960 that I'm from, where a lot of the original founders of Valisher are from. And we went and talked

00:13:47.620 to the industry, the big distributors and pharmacies and manufacturers. And it was a very odd

00:13:54.840 discourse because all these major players were telling us, yeah, you know, there are a lot of

00:14:00.300 problems in the system and it looks like the problems are getting worse, but it's not our problem.

00:14:05.300 It always ended up being somebody else's problem. And we also realized that there's actually seems to

00:14:10.320 be disincentives. The established industry actually looked closer at what's on the shelves. They may not

00:14:16.980 like what they see. And so this was really around now, end of 2017, early 2018. That's when we decided,

00:14:25.480 you know, we actually have to attach this to a pharmacy. So we already had the accredited laboratory,

00:14:31.300 controlled substance licenses and everything else around a laboratory. And then we built out

00:14:35.280 the online pharmacy component. And that launched just about a year ago.

00:14:39.800 And when I was referring to my skepticism, I guess what I was really getting at was in 2015,

00:14:45.580 if you had pitched this idea to me and said, Hey, I got this idea, which is we're going to actually

00:14:50.440 test individually every single drug that gets dispensed. I would have said, gosh, that doesn't

00:14:55.580 really sound like it's a significant enough problem. I mean, there's two issues with it. Is there

00:14:59.840 enough demand for it? I would have said no. And secondly, the scalability of that strikes me as

00:15:06.440 cumbersome and difficult. So maybe to give me a tangible example, if my doctor called me in a

00:15:11.700 prescription for 90 tablets of allopurinol, 300 milligrams of allopurinol, 90 tablets to last me

00:15:18.660 for three months, would you open a batch of allopurinol that you got from your generic supplier?

00:15:24.840 Let's say that batch that you got wholesale, how many tablets would that contain?

00:15:28.220 So you're actually getting to the exact root of the business plan of how to make this economical

00:15:34.280 is that at Valisher on the pharmacy side, unlike most other pharmacies that are going to be

00:15:40.520 buying every day or every week and are kind of just constantly looking for the cheapest possible

00:15:45.580 source and therefore also not having a lot of inventory, we buy large batches. So we'll look

00:15:51.460 six months out, usually at least to buy a lot of that medication upfront. So we have a larger batch of

00:15:59.080 it so that when we sample it, when we do all of our analytics, obviously that adds some cost,

00:16:04.880 but that cost is amortized over the larger batch. So per pill that you're buying from us,

00:16:10.820 it's not adding a whole lot of cost to us, especially as we have proprietary technology

00:16:16.180 that also allows us to do this in arguably some of the cheapest possible ways. And we really optimize

00:16:21.120 for it. But we're obviously making less money than your standard big name pharmacy that's not doing

00:16:26.780 any of this. But you're seeing that a lot in the world of online pharmacy these days, that there's

00:16:32.120 all these kind of value ads that are coming out there. So whereas our competitors are working on

00:16:38.180 spending money on specialty packaging or sending chocolates with your birth control pills, that

00:16:43.880 costs money too. Instead of spending money on that, we spend money on analysis. And it obviously cuts

00:16:50.600 into the overall profit margins, but we're still able to make money as a company and offer this,

00:16:58.760 what we certainly believe is a really critical service of analysis on that batch of medication.

00:17:04.160 I don't know if you ever heard the podcast with Catherine, but I believe in that podcast,

00:17:07.660 I tell a story about sort of the first time it occurred to me that generics, there might be

00:17:12.900 something wrong with a generic. And it was several years ago. And it was a patient who

00:17:16.280 I had prescribed Crestor, which of course got filled as resuvastatin, which is not uncommon at

00:17:22.680 all. That's the generic version of Crestor. And he had previously been on atorvastatin,

00:17:27.940 the generic version of Lipitor, but there was just, there was something I didn't like.

00:17:31.420 There was a blood biomarker I didn't, I wasn't happy about. And I thought before we abandon a

00:17:36.140 statin altogether, let's give it one more try. So we put him on an equivalent dose of resuvastatin,

00:17:42.320 which is usually half the dose. So I think if he was on 40 of Lipitor or atorvastatin,

00:17:47.120 I put him down to 20 of Crestor, which got filled as resuvastatin. Eight weeks later,

00:17:51.780 I get his blood back and he's back to his baseline level of ApoB, which is the thing that I'm tracking,

00:17:58.700 suggesting he's not taking his medication at all. Now I'm not a browbeating doc. So I'm very

00:18:03.680 straightforward with my patients. I just say, Hey, did you forget to take them? Did you run out like a

00:18:08.320 month before the test or what was going on? And he said, because, and if that were the case,

00:18:12.200 he would simply say, yes, I just, my patients are very transparent. And he said, no, no, no. I take,

00:18:17.440 I take this thing religiously. And I remember scratching my head and thinking, we know that

00:18:21.060 he is statin responsive. So there's something about this batch that could be different.

00:18:26.540 So I just had my team call in and insist that we get the branded version. We got it. He took it.

00:18:34.540 It worked. I sort of forgot about it. That type of thing happened a few times over the last few

00:18:39.860 years. And then of course, reading Catherine's book, I was like, Oh my God, the lucky times are

00:18:46.260 the times when we see the drug and it has a very obvious measurable response in a biomarker. But

00:18:52.740 then there's a whole other class of drugs for which that's not entirely true. Drugs like blood pressure

00:18:56.860 medications or seizure medications or antibiotics. In fact, most drugs do not fit in the camp of

00:19:04.260 a very clear biomarker. So when you set out to do this again, based on your friend's experience,

00:19:10.320 what did you expect to find? Because at the time you guys started, Catherine hadn't done her

00:19:15.020 complete investigative watershed expose of the mass fraud coming out of India and China. So

00:19:22.840 did you think this was a needle in a haystack problem, but you just wanted to give people peace

00:19:26.940 of mind? Or did you think this was a much larger systemic issue? Actually, when Adam called me about

00:19:32.140 the issues that he was seeing himself with anticonvulsant medication, I mean, obviously I

00:19:36.000 was concerned about his own health, but for a business definitely wanted to understand,

00:19:41.260 is this something more pervasive? And I myself was not on any medications at the time. So I had no

00:19:47.640 personal experience to relate it to and figured, Hey, as a scientist myself, let's look at the literature.

00:19:54.300 And there's a lot of literature out there, especially in certain areas like anti-epileptic

00:20:00.160 drugs. You start talking to neurologists, oftentimes, especially psychiatrists that see a lot of these

00:20:06.820 issues between brand and generic, between generic and generic substitution. And I recall even back then

00:20:13.180 that one of the papers that I looked at was a Harvard medical school study that had almost 2000

00:20:19.640 patients and showed simply the act of refilling your anti-epileptic medication was associated with

00:20:26.120 an over twofold increased chance of getting a seizure. And I'm like, wow, as a scientist looking

00:20:31.000 at this, like this sounds really serious. And especially in a kind of a class of medication where

00:20:37.460 it's so clear when your medication is off, you get a seizure. But to your point, this must be happening

00:20:43.460 in all sorts of medications where it's less clear. And once you really start talking to a variety of

00:20:49.340 different doctors, you start hearing it a lot too. Like it seems like a lot of doctors have at least

00:20:53.480 suspected it as a problem or have similar stories as you talk about. I know certainly in Catherine

00:20:58.960 Eben's book, Bottle of Lies, she talks to a couple of different doctors from the Cleveland Clinic that

00:21:04.100 have seen it in heart failure medications, in diuretics. And it's very hard to actually pinpoint

00:21:10.960 the exact problem and nobody's really looking and analyzing. So what we thought in the beginning

00:21:16.340 was at the very least in certain key areas, like anti-epileptic drugs, like antidepressants and

00:21:23.520 various others that are very big markets and a lot of people seeing these issues, that at the very

00:21:29.440 least there, we could have a lot of impact and start looking. But to answer your question, did we think

00:21:36.300 the problem would be as pervasive as we're already seeing? I don't think we quite predicted just how much

00:21:43.300 we'd be finding and how quickly and how the engagement of all this has just really, really

00:21:49.500 increased in certainly in the last few years. But if you look at it, there is a huge problem with

00:21:55.320 Welbutrin and Pupropion back in the late 2000s, 2007, 2008. There's a lot of these cases that have

00:22:02.760 happened. And I think a big part of what we set out to do and what we're actually hearing from these

00:22:08.360 doctors now is that there really just wasn't much that a doctor could do. It's either brand or generic

00:22:14.320 brand. You tend to trust more, but can't obviously afford very often. And then you have generic that

00:22:21.000 there's less and less trust in, but you can afford and essentially set out to create a validated

00:22:27.320 generic. So something that has actual chemical validation behind it, and you can still afford same

00:22:34.400 price as generic that you'd be buying anywhere else. Was the business model, and more importantly,

00:22:39.420 I guess your hypothesis, that this was a problem confined to the generic market? Or did you also

00:22:45.120 intend to check branded drugs? And did you, by extension, then assume that brandeds could be

00:22:50.380 susceptible to the same problems? I think that the general thesis was that this is probably worse

00:22:55.940 in generics than in brand. However, we had nothing to really back that up. And obviously the data just

00:23:02.120 didn't exist period for these kinds of things. So our intention was always to say, we don't know

00:23:08.460 exactly where these problems are going to be from, and we're not going to make any assumptions ahead

00:23:12.200 of time. Just everything needs to be independently tested at the end of the supply chain before a

00:23:18.260 patient gets it. And David, one last question really as far as background goes. You've alluded to the

00:23:23.340 fact that you have a scientific background, but specifically what is it about your background that

00:23:26.960 allowed you to come into this space and actually innovate? I'm a molecular biologist by training

00:23:32.660 at Yale University, and I spent most of my working time in the field of DNA sequencing. So in biotech,

00:23:40.380 essentially developing complex tools for analysis of complex problems. I spent eight years most

00:23:47.520 recently at a company called Ion Torrent, where I was one of the original technology founders there and

00:23:53.180 head of chemistry R&D. And we essentially had this concept that we would sequence DNA on a microchip.

00:24:00.140 It was based on some papers that we spent millions of dollars proving was just noise. But luckily we

00:24:05.740 had some other ideas in mind and had an amazingly innovative group of people there even early on

00:24:11.960 that were able to make it work. And Ion Torrent is now the number two DNA sequencing technology in the

00:24:17.580 world. So myself and some of the other key developers, even at Ion Torrent and folks that I've worked

00:24:22.780 with before, I think we're well positioned to develop some new technology, which is, again, how we saw this

00:24:30.060 problem originally being solved as something that we can develop and then just plug into the existing

00:24:35.740 system. And that's what we started off doing and then brought in some more folks to enable the pharmacy

00:24:42.220 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.

00:24:48.060 I actually get a call from one of my patients, the only one of my patients, who takes a medication,

00:24:52.540 called Valsartan, which is a drug called an angiotensin to receptor blocker. It's a drug that

00:24:59.400 we use in certain patients with high blood pressure. And in particular, this is a patient who all the

00:25:04.200 other boxes had been checked. Otherwise, a very healthy guy, but just couldn't get the blood pressure

00:25:08.640 where we wanted it. So here he was taking this medication and he said, hey guys, I saw something in

00:25:14.160 the paper today about some of these things being withdrawn. Should I be taking it? Tell me a little bit

00:25:20.100 about that and your involvement in that.

00:25:23.240 So Valsartan and Losartan and various other ARB medications or Sartan medications that have been recalled

00:25:29.940 over the last year, I think are unfortunately a very clear and visible case of how the system can go wrong

00:25:38.440 and how many cracks there are in it. The fact that this global supply chain is a self-reported has a lot

00:25:45.580 of visible fraud that's happened in the past. And really what happened with Valsartan was there was

00:25:51.740 a manufacturing change to save some money in China or other places overseas that are making the variety

00:25:57.860 of these different active pharmaceutical ingredients. And by having this manufacturing change,

00:26:04.080 they were creating all sorts of impurities. So these impurities themselves being extremely

00:26:10.380 potent carcinogens. One of them that I'm sure we're going to be talking more about is NDMA,

00:26:15.240 nitrosodimethylamine. It's actually talked about as a probable human carcinogen, but you have to keep

00:26:22.080 in mind that's only because you can't ethically have a study where you give humans a carcinogen.

00:26:27.280 And the data in animals is extremely clear. It's been studied since the 1950s. NDMA is literally one

00:26:35.500 of the best studied, most potent carcinogens known to man. It's actually used as a control

00:26:41.340 to induce cancer in rats. If you're doing a clinical study and want to make absolutely sure

00:26:46.200 that a rat's going to get cancer, you give it NDMA. So this was one of the contaminants that they were

00:26:50.980 creating in this process that they obviously didn't do the proper quality controls that they

00:26:57.900 were reporting to the FDA and went all over the world. And this happened for years. It was only

00:27:03.480 detected years later, I'm sure just kind of randomly. And then as people were looking more into it and

00:27:10.480 then actually overseas countries started recalling it, eventually it was also recalled in the United

00:27:15.220 States. And it was obviously a very real problem that even continues today. So we're talking about

00:27:21.940 it in 2018, summer of 2018 is when it started. The most recent recall in Losartan, I think it was

00:27:28.720 like a week ago. And we're in October, September here of 2019. And this continues to be a pervasive

00:27:35.940 problem. Before we leave this topic and get to what we really want to talk about today, which is Zantac

00:27:40.440 and Ranitidine. What is the take-home message for patients and physicians either taking or prescribing

00:27:46.260 respectively ARBs, this class of drug? It certainly seems like the problems even there are not over,

00:27:54.640 especially the fact that there's been recent recalls even now. We at Valisher are trying to be very

00:28:00.220 proactive about this whole space. We incorporated this kind of carcinogen analysis earlier this year. I mean,

00:28:06.640 we just launched the pharmacy at the end of 2018. Towards the beginning of 2019, we added nitrosamine

00:28:13.500 assay and incorporated the FDA recommended protocol for analyzing for NDMA and other carcinogens and

00:28:21.240 impurities. And we wanted to not just look where everybody else is looking. We also looked at other

00:28:28.800 seemingly obvious places to look. So when this manufacturing change happened, what the change was

00:28:35.980 is they changed solvents. And they started using this solvent called DMF, dimethylformamide.

00:28:42.520 Can you explain to people, David, what a solvent is and why it's necessary to make a drug or do most

00:28:48.660 organic chemical reactions with solvents? Sure. So a solvent is basically something that you're

00:28:55.060 dissolving different components of chemistry into in order to make a reaction. You can think of it like

00:29:00.700 cooking. If you're going to make a soup and you want a whole bunch of things in it,

00:29:03.420 your solvent is essentially water. Or even if you're cooking an egg, for example, there's so

00:29:08.800 many different ways to cook the egg. But if you change your solvent, if you change how you're

00:29:14.940 essentially cooking that egg, although it's still an egg, all sorts of other things can happen. So

00:29:19.520 what they really did in this case of Valsartan was they might've been cooking the egg in water for a

00:29:25.140 long time. And then all of a sudden they decided to switch to oil. If you've ever fried an egg,

00:29:29.820 obviously it tastes different than if you boiled the egg. And those differences are because of all

00:29:35.160 these side reactions and side products that are happening that give it different flavors and all

00:29:40.300 sorts of different properties. But yes, it's still an egg. So they were still making Valsartan,

00:29:45.140 the key ingredient they were trying to make, but there's just so much happening on the side that

00:29:49.920 they apparently were not doing the proper controls of trying to find out what's happening there.

00:29:54.540 And NDMA, true that it's hard to look for every possible contaminant that there exists. But again,

00:30:02.400 NDMA has been well studied. It's been talked about as a problem in pharmaceuticals since at least the

00:30:07.920 seventies. So seemed like a fairly obvious thing to look for. And for us, when we started seeing all

00:30:15.560 this, of course we were going to look for NDMA and DEA and a few of these other common carcinogens that

00:30:20.980 were being talked about as by-products of this manufacturing change. But we wanted to also

00:30:26.400 look for this new solvent. I mean, if you're going to cook the egg in oil now, there might also be oil

00:30:31.380 still on that egg. And that solvent, the DMF, dimethylformamide, is itself a probable human

00:30:38.840 carcinogen. It's in the same class of a carcinogen as NDMA. And this is a categorization from the World

00:30:45.120 Health Organization and the International Organization for the Research of Cancer.

00:30:48.540 So we started looking for that too. And as soon as we started looking, we found it all over

00:30:54.860 Valsartan. We found two-thirds of the manufacturers that were making Valsartan that we actually looked

00:31:00.100 at their batches at the time had hundreds of nanograms to over 100,000 nanograms of this DMF

00:31:08.880 contaminant, which is a probable human carcinogen. And so we put together an FDA citizen petition and filed

00:31:16.340 it with the FDA saying, listen, obviously NDMA is a problem and there's other problems out there that

00:31:22.900 are certainly a good idea to continue looking at. But the solvent itself is carrying over in this

00:31:27.860 system. And whatever these companies are doing to try and clean up their process, they're apparently

00:31:32.160 not even cleaning up the solvent. So it certainly underscores the importance of checking everything

00:31:38.300 and also checking every single batch. I mean, we had manufacturers that were clean sometimes.

00:31:43.420 And then another batch had not only very high levels of DMF, even had levels of NDMA that were

00:31:49.900 violating the FDA rules. So it certainly underscores the pervasiveness of the problem and certainly in

00:31:57.860 certain areas. David, some people who are familiar with the biotech industry will have heard a term

00:32:02.180 GMP. Do you want to explain what GMP means and what the implication is for something that's

00:32:07.540 manufactured according to that standard? Yeah. GMP standing for good manufacturing practices,

00:32:12.740 anything that's under FDA purview that touches the manufacturing process is required to be under GMP.

00:32:20.320 And it's essentially hundreds of documents and systems that are in place in order to make sure that

00:32:27.720 things are very well documented and done consistently and any errors or problems or manufacturing changes

00:32:36.120 like changing over your solvent, checking for contaminants, these kinds of things are all expected

00:32:41.640 to be part of the GMP process. And when you're following the whole GMP system, then it's supposed to catch

00:32:49.460 these kinds of issues. But this is certainly a very robust system. However, it's predicated on the

00:32:56.620 concept that you're going to self-report it to the FDA and that when the FDA comes and inspects,

00:33:03.260 they're going over these documents. They're not checking the chemistry of what's actually in that

00:33:07.700 pill. Is the implication here then that, well, let me just ask the question more directly. Is there

00:33:12.860 any evidence that any of the companies involved in the production of angiotensin receptor blockers,

00:33:18.400 drugs such as Valsartan and Losartan, actually were criminally negligent? In other words,

00:33:24.180 saw that their chemical processes yielded molecules that exceeded the acceptable limits of various

00:33:31.760 toxins and failed to report it? Or do you believe the evidence suggests that rather all of this was

00:33:37.820 simply negligence and oversight? Honestly, I haven't looked at that kind of evidence well enough to

00:33:44.120 answer directly. I would say either is certainly possible. It could have been maliciously covered up by

00:33:51.480 a manufacturer, or it could just be that they were saving a few pennies per pound of these kinds of

00:33:57.880 solvents and just didn't bother to look. I definitely don't have that answer.

00:34:03.180 I don't want to get too far down this rabbit hole because like I said, what I really want to talk about

00:34:07.560 is the most timely issue here, which is the ranitidine and Zantac one. So I apologize. I keep saying

00:34:12.220 we'll get to it, but, and maybe we can park this question, but it's a broader one, which says,

00:34:16.940 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

00:34:26.480 a person's body comes from a batch that has a certificate that demonstrates not only what's in

00:34:32.780 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

00:34:39.020 talking a lot about the oversight of drugs that are already in the market. Obviously a lot of what the

00:34:43.680 FDA is doing is looking at new drugs and the billion dollars that goes into developing something

00:34:49.180 new. I think the bottom line is that with limited resources, there's only so much you can do.

00:34:56.040 And a lot of what the FDA oversight is about is going through that GMP process and looking over

00:35:02.280 a bunch of paperwork that's being self-reported by the industry. And that obviously has limitations,

00:35:08.760 which honestly the FDA itself admits in a 2015 white paper direct from the FDA, A, they're saying

00:35:16.280 there's an unacceptably high occurrence of problems. And B, the FDA was saying that there's no formal

00:35:22.820 means for quality surveillance except through inspections. And inspection findings have not been

00:35:28.340 a reliable predictor of the state of quality. Those are pretty much direct quotes. So we at Valisher

00:35:35.900 and the original founders saw this as further underscoring of industry should be stepping in

00:35:42.020 and doing more. Why don't we actually analyze every single batch at the end of the supply chain?

00:35:47.460 FDA doesn't seem to have the resources to be able to do something like that,

00:35:51.160 but in the core of a new business model with some new technology and everything else,

00:35:55.260 we thought we could do it. There's more I want to talk about on that front,

00:35:58.540 but I think I'm going to save it until we get to the end of our discussion. So let's start talking

00:36:02.060 about this drug Zantac. So Zantac, the generic name for that is ranitidine has been around for

00:36:07.560 quite some time. I can't tell you how long it's been, but I certainly know it's been more than 20

00:36:11.140 years because it was among one of the most commonly prescribed drugs that I would have written

00:36:16.520 prescriptions for, for patients in medical school. It's an H2 blocker, which means that's one of,

00:36:23.180 there are three ways that you can reduce the acid secreted by the stomach. And this is one of those

00:36:28.600 ways is you can actually block the H2 receptor on the type of gastric cell that makes hydrochloric

00:36:35.400 acid. And therefore it became a very popular drug, not just for people with heartburn, but more

00:36:40.020 importantly, or at least as importantly, I suppose, even patients who didn't have heartburn, who were

00:36:44.820 undergoing hospitalization in whom one needed to reduce the burden of insult to their gastric lining.

00:36:51.140 So I don't even have the stats on how many people take ranitidine or Zantac in the United States.

00:36:57.520 Do you know those numbers, David?

00:36:58.720 The prescription ranitidine in 2016 was roughly 15 million. It was in the top 50 most prescribed

00:37:07.940 drugs. And obviously that's certainly a small percentage of the overall use being that it's

00:37:14.400 largely used over the counter by the brand Zantac or other various generics. Practically any pharmacy

00:37:21.940 that you used to go to, it's not there anymore, but pretty much every pharmacy had their own

00:37:27.180 versions and is one of the most common over the counter medications used certainly by millions of

00:37:31.920 Americans and folks over the world. Yeah. I've been fortunate in my life to not have heartburn more

00:37:36.800 than twice a year, but those two times a year, I sure took myself some ranitidine.

00:37:41.800 One other thing to mention there that was certainly a particularly high concern to us

00:37:45.920 is that the safety profile of ranitidine was considered so high that is one of the only drugs

00:37:53.300 prescribed to women while they were pregnant and given to infants for similar stomach issues.

00:38:00.200 Yes. My third child had reflux and he took a little liquid elixir of ranitidine for about three

00:38:07.680 months when he was little. And I also remember from doing my rotation in pediatrics, that was not an

00:38:12.700 uncommon thing to do. So tell me how you became interested in ranitidine. In early 2019, when we're

00:38:21.920 obviously responding to all these issues, as we've just talked about with Valsartan and other of these

00:38:27.580 blood pressure medications that had these carcinogen issues, it was obvious that we needed to incorporate

00:38:34.260 that technology and then be proactive. As we talked about, not just look for NDMA and the standard

00:38:42.320 carcinogens that others were looking for, but look for other common sense molecules and carcinogens at

00:38:48.740 the same time, but also at the same time, not just look at the blood pressure medications. So our whole

00:38:55.720 concept, of course, at Valisher is analyzing from every single batch of every single medication.

00:39:02.060 And ironically, ranitidine was pretty high in our list to go through the system because that same

00:39:07.840 friend of mine, Adam, his infant daughter also got a prescription for that elixir of ranitidine,

00:39:13.440 the syrup form. And as soon as we put it through the machine, following the standard FDA protocol at

00:39:20.480 the time, we were just floored by the results. It didn't seem possible what we were seeing on the

00:39:28.220 machine. And obviously we ran it a few more times and just consistently seeing millions of nanograms,

00:39:35.800 detection of millions when the FDA maximum permissible exposure to NDMA is 96. And again,

00:39:44.020 there's no safe level of this kind of carcinogen. The ideal level is zero and we were seeing millions

00:39:49.960 and that's how this all started. At some point, I'm sure it crosses your mind. There's a mistake here.

00:39:55.020 It's one thing if the FDA limit is 96, you're consistently seeing 100 up to 110, but you're seeing

00:40:02.180 five logarithms higher than an FDA limit. What's your self audit on that?

00:40:07.160 Gut reaction right away being a scientist is that something went wrong. Something got in there or who

00:40:13.800 knows, control went wrong perhaps and contaminated the column. The machines themselves we're talking

00:40:20.520 about don't get data wrong. I mean, these are forensic level machines. The machine specifically

00:40:26.640 is called a GCMS, a gas chromatography mass spectrometer. It's been the gold standard for

00:40:32.960 this kind of impurity analysis for decades, over 50 years. And so, you know, you start looking for

00:40:40.540 potentially human error or anything else. And I went to our chief scientific officer who brought this

00:40:46.680 obviously straight to my desk. Let's look through this system. Let's clean it. Let's run it again.

00:40:51.900 Let's run more controls. And we kept rerunning it and rerunning it and seeing the same thing.

00:40:57.400 It was very odd. But the other thing that we did at the same time was starting to look at the

00:41:01.500 literature. I mean, this is such an extreme finding. Five logarithms higher, five orders of magnitude

00:41:08.600 higher than what is even still not a good place to be. We started reading about this and there's been

00:41:16.220 literature about it for 37 years. So you're talking about it being out at least 20. The molecule was

00:41:22.500 approved in 1981. The first studies that came out that started raising concerns about NDMA and

00:41:29.100 ranitidine were published in 1982. It wasn't approved in the United States until 1983. And there was

00:41:35.640 literally decades of studies about the instability of the ranitidine molecule. There's 17 years of research

00:41:44.260 in the United States over the potential of ranitidine getting into the water supply and then forming NDMA

00:41:49.820 in drinking water. And they showed all sorts of instabilities in the molecule, reactions with chlorine,

00:41:56.140 with ozone, with all of these components that happen in a wastewater treatment plants, which are

00:42:00.620 pretty much benign for anything else. And that's when we also kind of came to the conclusion, well,

00:42:05.480 actually, if it's such an amazingly unstable molecule, perhaps it's just even breaking down

00:42:10.920 in the machinery that's meant to test these kinds of medications.

00:42:15.060 So does this mean that you were more leaning to the idea that this was not an issue specific to a

00:42:21.120 particular drug, meaning to a particular manufacturer, but rather to the drug? So when you looked at the

00:42:26.420 first sample where you see a million nanograms per dose, did I hear you correctly? A million nanograms

00:42:33.100 in a dose?

00:42:33.880 We were actually seeing between two and three million.

00:42:35.700 Okay. I'm guessing the first call you make once you decide this isn't a human error is somebody go

00:42:42.980 and get me branded Zantac. You got to think that this is a contaminant from the shady manufacturer

00:42:51.360 of this generic.

00:42:52.920 You got it exactly correct. At the same time as we're delving into the literature, we said,

00:42:57.660 okay, this is very odd about whatever was in this particular bottle, but let's just go to all of the

00:43:04.160 local pharmacies around us and buy exactly the brand Zantac. Let's buy all the various pharmacy

00:43:11.120 versions of ranitidine and test them all and get the cool mint version and the standard version and

00:43:18.880 the maximum strength and every single pill of every single manufacturer label or wherever it was coming

00:43:27.020 from, including the reference powder. So not only did we check every single bottle that we could get

00:43:32.940 our hands on at the time, we also bought the certified reference powder that's as pure as you

00:43:39.380 possibly can get it to rule out inactive ingredients or any interactions there. And even in the reference

00:43:46.000 powder, we are seeing millions of nanograms of NDMA being detected by this test.

00:43:52.880 Well, that's, I mean, that's problematic. I mean, that suggests that, let me, rather than tell you

00:44:00.000 what I think it suggests, what's your Occam's razor explanation for it at that moment? Meaning before

00:44:05.400 you do another assay, what does Occam's razor suggest is happening when branded generics alike

00:44:12.180 are containing millions of nanograms of something that should be completely absent?

00:44:18.260 I love Occam's razor and Occam's razor specifically said it's a problem with the drug. Everybody's head

00:44:24.380 has always been in this Valsartan and contamination and bad generics overseas and these kinds of things,

00:44:30.560 which are a problem too. But this was a problem must be at just a totally different level as in

00:44:37.300 the drug itself is just so incredibly unstable and not just unstable in terms of, okay, maybe you're

00:44:44.900 going to get a less potent pill. It's directly forming NDMA, the extremely potent carcinogen.

00:44:53.420 And actually one of the reasons that the specific data around these millions of nanograms was so

00:44:58.680 important, regardless of the conditions, and that's now becoming one of the discussion points,

00:45:04.400 is that there's no other way to get millions of nanograms, which is milligrams. I mean, these pills

00:45:12.080 are at 75 milligrams, 150 milligrams. So we're seeing milligrams of this carcinogen NDMA. There's

00:45:19.680 no other way that it could be there except if the molecule itself was reacting with itself and forming

00:45:27.380 it. There's no other source of nitrogen for this carcinogen, a very basic organic chemistry.

00:45:33.940 I want to double click on that for the listener who might be misunderstanding what you're saying.

00:45:37.020 This is such an important point that I'm a little floored. So a standard dose of ranitidine is 75

00:45:44.440 milligrams to 150 milligrams, correct? Correct. Okay. So, and again, just to state this for the record,

00:45:51.080 when you test a, call it 150 milligram tablet of ranitidine, you could discover, call it 1.5

00:46:00.440 million nanograms of NDMA. Yes? At least. Right. Which I didn't write it down, but I think that 1.5

00:46:08.760 million nanograms is 1.5 milligrams, right? Correct. Okay. So that means 1%, one full percent of the

00:46:18.280 supposedly active drug you're getting is a potential carcinogen. And by the way, I want to come back to

00:46:23.280 understanding the carcinogenic nature of NDMA, but let's park that for a moment. What you're saying is

00:46:28.300 just at a mass balance level, the only way you could get enough organic building block inclusive of

00:46:36.000 nitrogen to make NDMA is if you're taking some of it from the ranitidine, meaning it has to be an

00:46:42.680 almost decay or chemical reaction of the drug itself. Is that correct? Exactly. Exactly. And

00:46:49.660 from a chemistry perspective, that's extremely concerning. And I'll say one thing also that makes

00:46:56.400 it actually 10 times worse is that the NDMA molecule is a lot smaller or lighter than the

00:47:04.100 ranitidine molecule. So the molar conversion or the conversion of a ranitidine molecule into an NDMA

00:47:11.500 molecule is actually even more efficient than that 1%. The numbers are suggesting 10% or so conversion

00:47:18.600 of the ranitidine molecule into NDMA in an incredibly short period of time. So what we're talking about

00:47:28.800 in terms of this GCMS analysis is the way that it pretty much works is you have this vial where we

00:47:36.260 have a pill in it and some solvent. And then it goes into an oven, chromatography oven, where it's being

00:47:43.020 heated up. And then you sample the gas and run it through a column and then run it through a mass spec.

00:47:47.760 Long story short, you need to heat it up for a little bit to capture as many molecules as you can

00:47:53.080 that's coming off. And NDMA is a very volatile molecule. It goes into the gas. It's 15 minutes.

00:48:00.180 So it spends 15 minutes at 130 degrees Celsius, which is benign for practically any other drug that

00:48:06.480 we're looking at and is part of the FDA standard protocol. And for just these 15 minutes, which in

00:48:13.980 the chemistry world, there's very rarely do you have such a short reaction.

00:48:17.060 Yeah, that's like cooking a scrambled egg or cooking a fried egg in 10 minutes. That's pretty low temp.

00:48:22.260 Exactly. And usually if you're doing serious chemistry in a chemistry lab, you leave it for

00:48:27.180 hours or days and sometimes it requires weeks. But 15 minutes of exposure and you're getting around a

00:48:34.480 10% conversion into NDMA. That's incredible instability.

00:48:39.480 And again, the reason you're saying 10% for the listener is even though it's 1% by mass on a molar

00:48:46.020 basis, the way we actually count molecules, it's much greater.

00:48:50.240 Correct.

00:48:51.160 Let's pause for a moment and talk about NDMA. I certainly have a lot of questions about this.

00:48:55.720 You've already stated the formal name of the molecule. How big a molecule is it?

00:48:59.620 It's just a few atoms, right? It's a couple nitrogens and carbon and I don't have the molecular

00:49:06.780 weight in front of me, but it's pretty small. It's a tiny little thing.

00:49:10.280 Yeah. NDMA is categorized as a small molecule. It's particularly small, even amongst small

00:49:14.540 molecules. What is the mechanism by which it causes cancer in animal models?

00:49:19.920 Yeah. So NDMA basically sticks to DNA. It sticks to DNA. It modifies it. It's what it calls

00:49:25.780 alkylates it. It also oxidizes it. Long story short, it's very bad for your DNA. And by modifying

00:49:32.620 the DNA is what causes cancers.

00:49:35.220 Yeah. So sticking to DNA is not the worst thing in the world. I mean, methyl groups stick to DNA

00:49:39.180 all the time and that's called epigenetic modification, which can be quite bad, but can

00:49:44.320 also be completely inert and in some cases can be good. But this isn't just sticking to it.

00:49:49.680 It's changing the structure in the DNA in such a way that, well, presumably if it's a carcinogen,

00:49:55.060 the definition is it changes the DNA in a way that the DNA in that cell no longer responds to

00:50:00.780 appropriate cell cycle signaling. So now you have growth of a cell that can be unregulated as opposed

00:50:06.380 to regulated. How well is that documented? And in what model systems is that documented, both cell type

00:50:14.300 and in vivo versus in vitro? So the background in NDMA goes to at least the 1950s. I'll say that it's

00:50:22.520 extremely well documented in almost every clinical model, obviously other than human. In mice, rats,

00:50:30.900 cell assays, it's been heavily, heavily studied for decades. And like I was saying before, not just

00:50:37.880 studied, but also used actively as a control for inducing cancer in mice and rats.

00:50:46.140 Just to explain to the listener, in vitro means it causes cancer in a Petri dish where you take the

00:50:52.700 cells out. And if something does that, that's interesting, but it's a lot more interesting if

00:50:57.320 it can cause cancer inside the animal itself. And that's called in vivo. And that's what you just

00:51:02.360 said. Do you have a sense of what doses are necessary to induce cancer in rats?

00:51:07.720 So this part is also well studied. I don't know the exact dose, but what I can say is that the calculus

00:51:14.580 that the FDA has actually already gone through in terms of its potential effect on humans is based

00:51:21.540 on these exact kinds of animal models and studies. So during all the Valsartan and Losartan issues,

00:51:28.060 one of the statements that came from the FDA was that, well, if somebody had been taking the worst

00:51:34.440 case scenario of what they'd found, which I believe was somewhere around 17,000 nanograms or so of NDMA,

00:51:40.800 taking it consistently for years, there would be one additional cancer case in 8,000, which may sound

00:51:48.560 like a low number, but when you multiply that by the millions of people taking it, it's still thousands

00:51:54.200 of cancer cases that shouldn't have been. Obviously, there should be zero cancer cases that come from

00:52:01.220 carcinogens in your medications. And if you ask me, I'd say that number is concerning, period, to have

00:52:07.540 thousands of cancer cases. So those animal models are actually used to at least make a best guess

00:52:13.540 on what would happen in a human. And again, this is also best guess. It could be worse or could be

00:52:19.640 better. It's obviously not something you can test and to actually put inside humans.

00:52:24.780 But that doesn't seem nearly as high as some of the other carcinogens that we would expect. I mean,

00:52:31.280 there are other carcinogens that are used in laboratory testing that are guaranteed to cause cancer.

00:52:36.940 Is the difference you think the dose that in the animal studies when such agents are used,

00:52:43.820 they are used at astronomical doses, but not the same here? I mean, I'm going to tell you where I'm

00:52:49.820 going with my question in a moment so that you can think about it as you answer this question, which is

00:52:54.120 when you look at the ubiquity of Zantac use, the question is going to be where are the body bags

00:53:01.800 associated with Zantac? So before we answer that question, let's try to tease this idea out a bit

00:53:07.720 more if you don't mind. Sure. Definitely when you'd be doing a study with mice or rats and you're

00:53:14.000 trying to get them to have cancer, the dosage that those animals are getting is going to be much higher

00:53:20.680 than these trace amounts that are being found in the medications like Balsartan. I don't know

00:53:26.840 exactly what those dosages are, but I could imagine they're in the milligrams.

00:53:32.760 Interesting. So let's now talk about this epidemiologic question. I'm not a big fan of

00:53:38.360 epidemiology in general. I've sort of railed on epidemiology when it comes to nutrition, exercise,

00:53:45.480 so many things, which is not to say I think it is of no value, but I think one has to be very careful,

00:53:51.540 especially when you see sort of weak hazard ratios and try to infer causality. So when you see a hazard

00:53:59.200 ratio of 1.17, meaning there's a 17% increase in relative risk when exposed to X, and X can be

00:54:08.940 something you eat or something else. You know, I generally have a hard time with those things.

00:54:14.140 And if that is a statistically significant hazard ratio, it will have a confidence interval

00:54:18.680 that is well north of 1. So like the 95 confidence interval will not include the number 1. That's

00:54:24.300 how we sort of statistically get that. But I find epidemiology can be especially helpful when it's

00:54:28.800 not there. In other words, when epidemiology says there's no association between X and Y,

00:54:34.960 it becomes a lot easier to say there's much less likelihood that there's a causal relationship between

00:54:40.960 X and Y. So again, when you consider the ubiquity in size, 15 million prescriptions a year, plus I would

00:54:51.120 say easily three times that in over-the-counter use. So let's just call it 60 million dispensed

00:54:57.860 Xantex over-the-counter for almost 40 years. If NDMA is problematic, there should be a good collection of

00:55:06.600 body bags, shouldn't there? Definitely possible. And when we were putting the FDA citizen petition

00:55:12.000 together that we filed, we tried hard to look up. There are these epidemiological studies,

00:55:18.720 and we found one from 2004 published by the National Cancer Institute, where they looked at the antacids

00:55:27.600 at the time, the prescription antacids at the time when the study started in 1986, I believe. And they found

00:55:34.320 a link to bladder cancer when looking at those antacids, which were both reninidine and seminidine

00:55:41.180 at the time. And so it's kind of a, as far as epidemiology goes, obviously you want to look at

00:55:46.940 the individual drugs, not have them lumped together. But that was particularly concerning for us thinking

00:55:53.140 about another study that was done by Stanford University and published in 2016, which was the

00:56:01.100 only clinical study that we could find where somebody actually gave people a pill of Zantac,

00:56:06.600 and they found over 40,000 nanograms of NDMA in their urine. So we may want to talk more about that

00:56:13.280 in a second. But to answer your question about the epidemiology is essentially, it was just so assumed

00:56:19.360 that this is such an incredibly safe drug that at least as far as we could find that there just wasn't

00:56:23.640 much of that study out there. However, we have been working with a number of folks at Memorial Sloan

00:56:30.720 Kettering Cancer Center. And there's been for at least a few months now, a lot of efforts led by

00:56:36.500 Lior Bronstein to look into exactly that question. I mean, obviously, as you know, to do a full breadth

00:56:44.040 epidemiological study, I mean, these can take years, but we are looking forward to hopefully get the

00:56:49.980 initial results from Lior Bronstein and his team as soon as we can get them published in the journal.

00:56:56.460 And so what it really suggests is if there is an increase in the risk of human cancers from the use

00:57:02.020 of this, it's not going to be a la smoking. I mean, it's important, I think, for people to understand the

00:57:06.880 magnitude of risk here. In the case of cigarettes and lung cancer, the hazard ratios, depending on the

00:57:14.400 epidemiologic studies that were done, I think they varied somewhere between 8x and 14x. And I could

00:57:21.440 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

00:57:27.160 certain dose threshold of cancers, your risk of lung cancer is somewhere between 800 and 1400 times

00:57:34.440 higher than a non-smoker. In the words of one of my good friends, who's almost assuredly paraphrasing

00:57:40.860 someone else, when you don't need statistics to see the answer, that's usually a scary thing. And

00:57:46.840 that was certainly one of the cases. You didn't need complicated statistical models to tease out

00:57:52.820 the relationship between tobacco and lung cancer. Now, that does not mean, because Zantac obviously

00:58:00.080 doesn't fit that, I mean, I just, I can't imagine we wouldn't see some signal, but it could have a hazard

00:58:05.360 ratio of 2, meaning it could double your risk of a cancer. And because it's so ubiquitous, and if it's

00:58:12.580 doubling a cancer that is itself ubiquitous, that's the fear. Let me explain why to the listener, because

00:58:20.100 obviously you would get this, David. The reason that lung cancer was easy to spot from smoking is lung

00:58:27.360 cancer absent smoking is quite rare. So epidemiology is at its finest when the signal is huge,

00:58:34.960 and the thing you're studying is unusual. And that's why I believe epidemiology is almost as useful as

00:58:42.020 a warm bucket of hamster vomit when it comes to studying nutrition. Because when we study nutrition,

00:58:46.620 we're interested in the diseases of civilization, diabetes, obesity, and things like that. But the

00:58:52.380 problem is those things are so ubiquitous. I mean, there is so much of those things that it's very

00:58:58.380 difficult to pick up signals associated with lifestyle factors. So I guess what I'm trying to get at,

00:59:04.280 and feel free to disagree with me. I'd like for you to disagree or refine my thinking,

00:59:08.240 but I'm trying to make sense of this on two levels. One, how big a problem is this? And two,

00:59:15.220 what are our blind spots? I think you're basically saying we don't know how big a problem this is,

00:59:19.740 and that's the fair answer because the study hasn't been done. We haven't looked at the cases and the

00:59:24.520 controls, meaning the people who have taken it and the people who haven't. But the magnitude problem

00:59:29.100 and the blind spot problem really come down to, we will not know the answer until we figure out

00:59:34.920 which type of cancer is. Because if it increases the risk of a very rare cancer, I suspect it would

00:59:40.660 have shown up. I just think if there was a huge uptick from 1980 until today of some very rare cancer,

00:59:48.440 that would be a lot easier to point to an environmental contaminant such as a drug.

00:59:53.800 But if it's increasing the risk of breast cancer and prostate cancer, which are large cancers to

01:00:00.800 begin with, it would be harder. Do you agree with my assessment? I know you're not an epidemiologist,

01:00:04.980 but you're a clever guy and you've thought a lot about this and you've thought about it more than

01:00:08.220 I have. Well, I think it's going to be a very interesting conversation to get back to when the

01:00:13.460 results are published. And I will say that the big problem I think that's certainly underscored with

01:00:20.880 this ranitidine issue is that just nobody was looking. You could argue that how would they

01:00:25.640 have known where to look, which I can also point towards lots of studies and information of should

01:00:32.840 have been looking at NDMA. But nobody was obviously looking for the NDMA before and nobody's been looking

01:00:38.640 at the epidemiology before. There have been a number of rare cancers that have gone up that have been

01:00:43.820 unexplained, some of them starting in the 1980s. So let's defer that question for when there's more

01:00:51.040 data, of course. And I think this is something that is going to take years to really get down to

01:00:57.680 what is the total impact for real. But I can't imagine it's going to be zero. And anything greater

01:01:05.100 than zero multiplied by the millions of people taking it for 40 years nearly is a tragedy.

01:01:11.360 Especially when you consider that there are no shortage of substitutes that are equally efficacious,

01:01:17.580 if not better. I mean, that I think comes down to, it's one thing if this were the only drug out

01:01:23.520 there that could treat patients with HIV, in which case you have to weigh out the benefits of a drug

01:01:29.300 versus the costs. But when we're talking about reducing gastric acid, which again, there are more

01:01:35.140 drugs in that category than I can certainly count, it begs the question why. Now, I want to go back to

01:01:40.320 something you said. So you brought up the study by Zhang and Mitch in 2016 at Stanford. I never heard

01:01:46.380 of that study until I started looking into this Zantac ranitidine story. Presumably, you hadn't

01:01:53.400 either until you made your discovery and went back. Why did the Zhang and Mitch article not get more

01:01:59.840 attention given the largely accepted carcinogenic nature of NDMA and the, I mean, staggering nature of

01:02:07.160 the study. If I recall the study, one pill, 150 milligrams given to subjects overnight who had been

01:02:12.880 not taking it before and you just collected the urine and you found, I don't know, was it 40,000

01:02:18.540 nanograms of NDMA? Right. Over 40,000 nanograms in urine, which in and of itself sounds really bad and

01:02:28.040 obviously it is, but it's actually at least a hundred times worse because the renal clearance of NDMA,

01:02:35.120 so how much NDMA actually makes it into the urine, is that often 1% or less. And that's because

01:02:42.900 NDMA sticks to DNA and your body is full of DNA and it's reacting all over your body. And so very

01:02:50.000 little of it is actually expected to make it to the urine. So really what those results were suggesting

01:02:56.520 is that somewhere around 4 million or millions of nanograms of NDMA are being exposed in your body,

01:03:05.040 with a single pill of Zantac. And they were using the brand Zantac in that particular study,

01:03:10.820 which again, loops back into our results that we were seeing at the lab conditions, also of the

01:03:16.760 potential of this molecule to form millions of nanograms. So totally agree with you. It was an

01:03:22.260 extremely eye-opening study. And to go back to when we at Valisher were originally finding this

01:03:29.180 problem and Corey Kuchera, our chief scientific officer, brought it to my desk and we started

01:03:34.960 looking at the literature. That was, we were not aware of that study beforehand, but as soon as we

01:03:38.920 saw that study, we're like, what? Like this is, this is an extremely alarming study.

01:03:44.460 Yeah. And it sort of validates your numbers because if one pill is putting 40,000 in the urine,

01:03:50.240 as you said, you could assume that there was 4 million in the bloodstream. That's the same order

01:03:56.240 of magnitude as what you found in your chemical analysis, which may or may not be compromised

01:04:01.600 by temperature, which we'll come back to. So why didn't that study get more attention is my question.

01:04:06.980 I mean, honestly, Professor Bill Mitch, great guy that is in the environmental sciences. So he'd been

01:04:13.760 looking at this ranitidine problem himself at Yale University, at Stanford University for 17 years.

01:04:19.960 I mean, his first papers published in 2002 were concerned about where does NDMA come from when

01:04:28.160 it's in drinking water and coming out of wastewater treatment plants. And the irony of how this all

01:04:34.200 came up for him was actually that there's this big environmental problem where they had this rocket

01:04:40.300 fuel plant where NDMA is often a by-product of rocket fuel manufacturing. And they were dumping into

01:04:46.960 a river and all of a sudden there's all this NDMA in drinking water and a lot of attention to NDMA,

01:04:53.940 a very well-known carcinogen. But what they found is that even after they cleaned it up and even after

01:04:58.960 they started looking in other cities, they were still finding low levels of NDMA. It basically sparked

01:05:04.440 the 17 years of research for Bill Mitch and all the various folks that he's been working with and in

01:05:09.480 this field of environmental science of water quality. And I think this has been like this big

01:05:15.180 red button serious problem in a more obscure science than the medical community is used to.

01:05:22.500 You know, I'm sure yourself as a doctor, I try to keep up with a variety of journals or scientific

01:05:28.160 findings, but I don't know how often you're looking up environmental journals.

01:05:32.520 I can tell you the answer to that. It'd be never.

01:05:34.740 Right. Right. And look, I think what we found ourselves in the position at Valisher was adding

01:05:41.740 some new science, some new discoveries that we found, but really we were just connecting the dots

01:05:46.600 over 37 years of research. And what was very clear also in Mitch's paper of that specific study was that

01:05:55.860 there was some sort of missing biological link because there's also been a lot of work which we also

01:06:00.660 recreated, which Bill Mitch did as well, looking at the stomach, just conditions of the human stomach.

01:06:06.360 And you tend to find hundreds of thousands of nanograms of NDMA, which is also very bad being

01:06:12.700 formed by the reninidine molecule. But his study was pointing to the possibility of millions and

01:06:20.080 therefore reninidine forming even outside of the stomach and the body being extremely complex,

01:06:26.220 which drove us at Valisher to look more towards, well, is there a potential biological link here as

01:06:32.800 well? And we identified an enzyme, specifically DDAH1, but this enzyme has also been well-characterized

01:06:40.900 for many years. And what it does is it just grabs onto a molecule and it breaks off this DMA group.

01:06:47.520 So NDMA is the N and the DMA components. And once you break off a DMA, it's very easy to form the NDMA.

01:06:54.440 There's nitrite that freely circles in your body and lots of other ways to make it.

01:06:59.900 And so essentially we looked at this enzyme and did computational modeling to find that seems that

01:07:06.420 the reninidine molecule fits extremely snugly in this enzyme. And that at least gives a potential

01:07:13.260 biological mechanism for forming millions of nanograms throughout the body, even outside of

01:07:18.500 the stomach. We essentially had now that biological link and the chemistry side, and then all the way

01:07:25.220 into the full body clinical study that Bill Mitch did that makes a very compelling story that reninidine

01:07:32.620 is just a toxic molecule in the human body.

01:07:35.400 So let's talk about the FDA's response to all of this. What was the first date you made public your

01:07:41.360 findings?

01:07:41.740 So we actually confidentially alerted the FDA back in June. I don't recall the exact date.

01:07:48.740 We filed an FDA citizen petition that made our much deeper analysis with the biological link and

01:07:55.220 everything else that we were studying. We filed that September 13th. But we did, even without having

01:08:01.780 the full story yet, we thought the results were so alarming that we did this kind of confidential

01:08:07.520 filing to the FDA. We didn't want to be publicly talking about these kinds of problems if we didn't

01:08:13.440 have the full story. Obviously, cognizant that this drug industry can be extremely litigious. A lot of

01:08:19.080 lawyers don't like it if you're talking about a particular drug badly. So that's when we did the

01:08:24.100 initial alert and continued to analyze this. And then, obviously, the FDA made their own announcement

01:08:29.520 also September 13th.

01:08:30.840 So the September 13th date you filed the citizen's petition was the date that the FDA said that

01:08:36.460 trace amounts, well, actually, I don't have their statement, but do you know exactly what they said?

01:08:41.580 I mean, I remember reading it because at that level, it starts to even get it. Even guys like

01:08:45.500 me will start to see it when the FDA is saying it. But how did they word their response to the

01:08:49.700 citizen's petition?

01:08:50.940 So the FDA's statement Friday the 13th, September the 13th, was, and I don't have the exact wording in

01:08:58.560 front of me, but that they had found an impurity in DMA at low levels. I think they made some

01:09:05.340 references to barely exceeding those that's in food. Kind of feels like no big deal, but they're

01:09:11.580 still making an alert and wanted everybody to be aware of that. And us, we've been working for months

01:09:17.460 now on this issue and putting together this citizen's petition that has all the information that we've

01:09:23.840 studied about the chemistry, the biology side of the components, a bunch of citations of as much as we

01:09:30.140 could find in terms of epidemiology. But we also had Lior Bronstein and Morris Lone Kettering, folks

01:09:36.440 there working on the epidemiology, which we thought that's going to be the full story that we wanted to

01:09:41.500 publish as a complete document. And we were actually quite taken back by the fact that the FDA made this

01:09:48.100 kind of announcement on September 13th. And although the citizen petition wasn't complete yet with

01:09:54.520 epidemiological results, we felt that it was very important to publish it, get it on file and have

01:09:59.440 everybody see the full story that includes these very alarming findings on the chemistry and biology and

01:10:06.340 underscoring Bill Mitch's study, which all these things, even just by themselves, are so incredibly

01:10:12.060 concerning that even though we didn't have the epidemiology done yet, we definitely felt should be

01:10:17.900 published. Now, the FDA has the authority to do a lot. I certainly learned what they don't have the

01:10:24.140 authority to do in talking with Catherine Iban. But did they have the authority on September,

01:10:29.920 since it was a Friday, let's give them the weekend to think about it. But on September 16th,

01:10:35.100 that Monday, did they have the authority to pull all forms of ranitidine and Zantac off the market in the

01:10:41.220 United States? I believe they do. They definitely, at the very least, have the authority to request

01:10:46.400 manufacturers recall it. When you hear about recalls, it's almost always voluntary recalls,

01:10:52.920 but the FDA can push for it. Interesting that you mentioned that the following Monday or Tuesday of

01:10:58.240 that week, that's when the first other health system, Canada, so Health Canada made a statement

01:11:05.000 September 17th, that Tuesday, with a very strong message of requesting all companies to stop distributing

01:11:12.420 all forms of ranitidine. And the second line in that statement was, current evidence suggests that

01:11:19.600 NDMA may be present in ranitidine regardless of the manufacturer, which directly underscores what we

01:11:26.580 were finding, that it doesn't matter how it was made or where it was made, just that the drug itself

01:11:32.700 is so incredibly fundamentally unstable that it can directly form NDMA in a whole variety of conditions

01:11:40.300 and should just be taken off the market. Yeah. Well, I'm Canadian. I'll take a little

01:11:45.000 victory lap on the conservative nature of Health Canada. Totally kidding. How many countries besides

01:11:50.140 the great nation to the north of us have followed suit with Canada? So to date, now we're still just

01:11:58.080 only a few weeks away from this September 13th announcement, roughly 30 countries have recalled or

01:12:05.620 banned ranitidine. And I mean, not just places like Italy and France and Germany, but you have Kenya,

01:12:13.900 Libya, Bangladesh, Saudi Arabia, Pakistan. Pakistan actually came out not just recalling all ranitidine

01:12:21.980 products. They actually told all the manufacturers in their country to stop making it, as in stop

01:12:28.020 everything you're doing with anything related to ranitidine. Stop it. And that was in Pakistan.

01:12:33.360 I mean, I just don't even know how to make sense of this, David, to be completely honest with you.

01:12:37.500 So I sort of get Canada's reaction because they were the first to react and they reacted before

01:12:44.340 the FDA had done what they've done over the past few weeks. Do you think a lot of these other countries

01:12:49.960 are just in a herd mentality mode or do you think they've independently taken a look at your data,

01:12:54.820 your petition and come to the same conclusion? I know that's an odd question, but the real question

01:12:59.860 I'm getting at is why has the FDA resisted taking stronger action?

01:13:05.260 Each country has obviously their own health systems. I think a lot of these health systems

01:13:10.040 certainly look towards the FDA, but we were contacted by a number of press that were also

01:13:16.960 talking with the health agencies in their countries. We talked extensively to folks in Switzerland and

01:13:22.560 Germany and Poland, in India, in Russia. And it seemed that quite a few agencies were running their

01:13:30.840 own tests. We know specifically in South Korea, they even published some of those results. They were

01:13:37.560 finding at minimum 2,800 nanograms of NDMA and their worst was 32,000 nanograms of NDMA that was found by

01:13:46.400 South Korea's regulators. And these numbers in of themselves are obviously not good. But I think one of the

01:13:55.560 unfortunate things that happened out of the FDA's original statement is that it made this whole thing

01:14:02.620 just sound like a contamination. And I think you saw this a lot with countries too, is that some of them like

01:14:10.300 Canada, I think realized early on, perhaps seeing our petition, or just looking at some of the data, like Bill

01:14:17.100 Mitch's study, that this is an inherent problem with the drug, and therefore stop all manufacturers, stop all

01:14:23.220 distribution. Whereas some other countries were banning certain manufacturers that maybe they tested, or they had

01:14:30.740 some data suggesting that this manufacturer had some level of contamination in it of NDMA. But even that

01:14:38.820 contamination, maybe we'll talk more about this of contamination versus inherent instability. There's

01:14:43.440 actually a great article in India that talked about this of why has France and Germany banned this

01:14:49.200 substance versus, at the time, India and the United States had not. And then a lot of what they were

01:14:54.520 concluding is that some people are looking at this as a contamination that maybe happens here and

01:14:58.720 there. And some are realizing that the reality that ranitidine is a fundamentally unstable molecule and

01:15:04.760 could certainly cause contamination as a byproduct of being unstable, but has a seemingly very high risk

01:15:11.960 of forming tremendous amounts of NDMA in the human body and should just be taken out completely off the

01:15:16.100 market. So the FDA released a statement in early October that basically said to the effect, hey, we're

01:15:23.260 going to continue to test ranitidine and its products. We're not saying there's nothing wrong here, but they

01:15:28.660 did very specifically challenge your method for testing. And they said specifically, and this I do quote,

01:15:35.780 it is not suitable for testing ranitidine because heating the sample itself generates NDMA. And presumably, they

01:15:43.940 mean heating it to the low temperature of 130 degrees Celsius.

01:15:47.260 Right. So yeah, that exact quote, heating the sample generates NDMA. I mean, they don't mention us

01:15:52.900 specifically, but they do say third party laboratory, which ironically in the press, I don't

01:15:58.800 think they even bothered talking about that. They just inserted the name Balisher. But I think at the

01:16:03.860 very least nicely underscores that even just some heat, which again is benign for practically all these

01:16:10.640 other molecules is enough to generate NDMA. So yes, exactly. We agree. Heat that could be happening

01:16:19.020 anywhere in transit, could be in a hot car or anywhere else, could directly degrade this molecule,

01:16:26.120 not just into falling apart, but into falling apart directly into NDMA.

01:16:30.700 So how do we get to the root of this problem? Because this could end up being the jugular issue.

01:16:34.880 I mean, in many ways, the Zhang and Mitch study suggests you don't need heat. Has the FDA commented

01:16:39.940 specifically on that study?

01:16:41.760 Not that I'm aware of. There's plenty of studies out there that look at all sorts of other conditions

01:16:47.480 that degrade ranitidine. Like they're not even looking at in general, they're just saying,

01:16:51.920 okay, here's ranitidine and let's see what happens when we add ozone that is commonly emitted by all

01:16:58.700 sorts of devices and things, or chlorine that you use for cleaning all sorts of things. And it also is

01:17:05.160 used in wastewater treatment plants. And even the reaction mechanisms were specifically ironed out

01:17:10.800 chemically of how ranitidine degrades directly into NDMA with these relatively minor and benign

01:17:18.880 conditions. And certainly the condition that concerned us at Valsher the most was the conditions

01:17:25.720 of the human body. So yes, we, in the introductory paragraph in our citizen petition, also comment on

01:17:33.240 how the FDA method that we use, that was the method available at the time for the analysis of NDMA,

01:17:38.700 we suspect that this 15 minutes of 130 degrees temperature is causing an incredibly efficient

01:17:45.800 reaction of generating NDMA from ranitidine. And so therefore we modified that particular protocol.

01:17:54.380 And I should also say that Valsher, apart from having some great scientists that work with us,

01:17:59.600 we are an ISO accredited facility specifically for the analysis of NDMA. So we modified the protocol,

01:18:06.720 did the proper controls and put down the temperature. So we developed another method still using the GCMS

01:18:14.060 and essentially copying the rest of the FDA protocol, and then bring down the temperature to body

01:18:19.320 temperature. And in this specific way of analysis, we didn't find NDMA in the tablets that we were

01:18:25.820 looking at. And so we used this low temperature version to analyze conditions of the human stomach,

01:18:33.200 actually very similar, almost exactly the same conditions that Bill Mitch was using in his study,

01:18:38.960 and others have used it in other studies before, where essentially we have simulated gastric fluid and nitrite

01:18:44.180 present, which seems to be particularly capable of reacting with ranitidine in your stomach, and is just

01:18:50.660 present in a lot of foods in general and in the human body, even without those foods. So we created those

01:18:57.300 conditions, put one pill of Zantac into essentially 100 milliliters of this kind of stomach fluid,

01:19:04.000 and then using the low temperature system, analyzed that and found very similar numbers as Bill Mitch

01:19:11.220 was finding is in the hundreds of thousands of nanograms of NDMA. So we found up to 300,000 nanograms,

01:19:18.280 Bill Mitch's study found up to 400,000 nanograms. So pretty similar results,

01:19:23.220 a very high formation of NDMA in a body relevant condition.

01:19:28.920 So David, let me just make sure I understand that. So obviously the GCMS gold standard,

01:19:35.220 you can't get around it, you have to be at 130 degrees Celsius in the oven to incubate it,

01:19:40.760 that's going to produce the numbers we've discussed. But you're saying you came up with

01:19:44.060 a different test, which is instead of just taking the pill, crushing it, sticking it into the GCMS,

01:19:49.000 you dump it into a 37 degrees Celsius bath that is modeled after gastric secretion. So it'll have a

01:19:55.700 pH of two, and it'll have this and that other cofactor and enzyme. And you're saying when you

01:20:01.020 took that little soupy bath, you did not have to put it into the GCMS, or you did, but you just ran

01:20:09.380 it at 37 Celsius instead of 130. I want to make sure I understand how you can do a low temp assessment.

01:20:15.260 Yeah. Important question. And that's somewhat of the annoying part of where this discussion has now

01:20:21.380 gotten to with these statements is now the devil's in the details. So, okay, what you described is how

01:20:27.900 we prepared the sample. So the kind of this bath that's emulating stomach conditions. And to analyze

01:20:35.420 that bath, we had to put it still in a GCMS, but now a low temperature profile of the GCMS, which

01:20:42.800 what that does when you lower the temperature in a GCMS is you've gotten less sensitivity.

01:20:49.400 So instead of being sensitive down to 25 nanograms, which is what the FDA protocol gets and that they

01:20:55.440 published and what we were getting in terms of the sensitivity when you use 130 degrees,

01:21:00.780 when you take it down to body temperature, now you're at a hundred nanograms of sensitivity.

01:21:06.660 So a little bit less sensitive. So obviously if you're trying to be a good chemist, you would put

01:21:11.860 it up to 130 degrees and get the highest possible sensitivity, which I'm sure is why the FDA published

01:21:18.960 that protocol at 130 degrees. And again, it's fine for valsartan and almost every other molecule that

01:21:24.460 we've ever looked at. Why is that the case? Why was it fine to go to 130 degrees Celsius with

01:21:30.160 valsartan? Valsartan is not unstable. In other words, the NDMA in valsartan is thought to be a

01:21:36.740 contaminant and not a product of degradation? Exactly. Okay. So can you run the GCMS at 37

01:21:44.820 Celsius? And is that what you're saying? You can, but you can only detect down to a hundred nanograms?

01:21:49.940 Correct. Exactly. So this is splitting hairs here, but who cares when you're dealing with a

01:21:55.280 concentration as high as you're dealing with, right? Exactly. And who cares when there's already

01:22:00.840 a clinical study that was done? We can argue all day about the conditions of the stomach,

01:22:06.400 of various things. You can never recreate biology, right? As soon as we're talking about biology

01:22:11.660 instead of pure chemistry, which is when the data of using the FDA protocol and seeing milligrams of

01:22:18.140 NDMA form from reference powder of ranitidine, that's chemistry analysis. So our conclusion from that

01:22:25.000 is that ranitidine is incredibly unstable, can form milligrams of NDMA in 15 minutes.

01:22:32.180 And there's no other way you could have done this except from the source of the drug itself.

01:22:37.060 As soon as we start talking about biology and stomach conditions, really the ultimate test there

01:22:42.900 is a clinical test where you go through the entire human body, which is exactly what Bill Mitch did at

01:22:50.020 Stanford University. Although did he use 130 degrees Celsius on the GCMS on the urine? Because

01:22:57.780 the real gold standard might be, or I wouldn't say the real gold standard, another elegant test would

01:23:02.500 be you take a person, you give them ranitidine, you collect the urine, and without doing anything,

01:23:07.700 you run that urine at 37 Celsius. And if that showed what Mitchell found, or even close to it,

01:23:16.180 if Mitchell found 40,000, let's just say you found 4,000. Let's just say that the difference between

01:23:21.060 37 Celsius and 130 Celsius on the breakdown product, because again, the question, we don't,

01:23:26.120 what we don't know is, is this person peeing out some byproduct of ranitidine that then further

01:23:31.240 decays to NDMA, or are they just peeing out straight NDMA? And if they are, then the temperature

01:23:37.200 should make very little difference in how much you detect, correct?

01:23:41.140 Right. Actually, when we saw Bill Mitch's study, and also seeing what we were seeing in the GCMS,

01:23:47.940 we called Bill and started asking him about his work and everything else. We were pushing on some

01:23:53.380 of those questions as well. He wasn't using the FDA method, but obviously the devil's in the detail of

01:23:58.980 all these methods. And he went back and did some significant controls to validate these kinds of

01:24:06.500 systems, what's something being created in the instrumentation. And after all of his validation,

01:24:12.280 he was still seeing over these 40,000 nanograms of NDMA.

01:24:17.400 So how confident are you? And again, the answer can't be 100%, or you wouldn't be a scientist,

01:24:23.040 which I know you're a scientist. So how confident are you that grossly elevated levels of NDMA

01:24:30.260 are being made from ranitidine that is not at all an artifact of instrumentation, human error,

01:24:37.780 or most importantly, temperature contamination?

01:24:41.580 Extremely confident. And you hit it on the head that as a proper scientist, I can never be 100% on

01:24:46.780 anything, of course, but the data is just overwhelming. And the other part of this is,

01:24:52.140 as you've mentioned before, this isn't some life-saving drug that there is no alternatives for,

01:24:58.860 where we say, you know what, we're 99% sure, but there's 1% that maybe we're a little bit off here,

01:25:05.300 and people depend on this for their lives. And let's think about that versus the fact that they

01:25:10.980 may cause some cancer over time. That's not the case. Plenty of alternatives, as you've mentioned,

01:25:17.320 this is not a life-saving drug. So I don't see how any of that calculus plays into thinking that

01:25:24.340 this should just be taken off the market. Yeah. And I would add another layer to that,

01:25:28.420 which I guess is why I wanted to speak with you about this, is I have a little bit of a background

01:25:34.000 in risk, in a formal training in risk. In risk training, one of the things you're always taught

01:25:38.680 to look for is asymmetry of risk. So if you have a bet, if you bet somebody $10 on the outcome of

01:25:46.460 something, so you put $10 in, they put $10 in, that's not a very asymmetric bet. You're going to

01:25:51.860 win $10 and therefore walk away with $20, or you're going to lose $10 and lose your money.

01:25:56.380 Those are great bets to make because you have a sense of what the downside is and what the upside

01:26:00.820 is. But what I really struggle with here, David, is this is a very asymmetric bet that the FDA is

01:26:07.260 making. There's a chance you're wrong. There's a chance that in a few years, all of the data will

01:26:14.080 be in, including what I consider arguably the most important data, which will be the human

01:26:18.600 epidemiologic data that tracks the cases and the cohorts. And it will show that Zantac is totally fine.

01:26:25.220 And further chemical analysis will reveal that there is some error in the methodology that you

01:26:30.940 and countless others have made. Doesn't sound like that's the case, but it could be. In that case,

01:26:36.940 the FDA will have been the hero for not recalling the drug. What's the upside in that situation?

01:26:44.060 Conversely, in five years, if the epidemiology or two years or whatever suggests the opposite,

01:26:50.160 which is this totally unnecessary, ubiquitous drug increased by two and a half fold,

01:26:59.040 a risk of cancer of fill in the blank cancer. And when the FDA was notified of this, they did

01:27:05.420 nothing. That's a very asymmetric downside. That downside is infinitely greater than the upside

01:27:12.100 of having done nothing. If anybody at the FDA is listening, I'm sorry if I sound like I'm being a

01:27:18.420 jerk, but I can't help but ask, what is your chief risk officer telling you right now?

01:27:23.480 Because if I was your chief risk officer and I didn't know a thing about biology,

01:27:28.100 I'd be explaining this to you. Where is that discussion, David? Do you know enough about

01:27:32.240 the FDA to understand that? Do they have a chief risk officer?

01:27:34.660 We have had no interaction with the FDA throughout all this, other than our submitting of the citizen

01:27:42.900 petition and seeing what they're saying about us in these statements?

01:27:47.200 Huh. Well, I guess the only thing I can tell you is here's what we've done. We've told that we have

01:27:52.460 three patients in our practice that take Zantac. So the first thing we did when I really figured out

01:27:56.940 how serious this was, which was not on Friday the 13th, by the way, the front of the 13th,

01:28:00.620 I took the FDA's word for it. Stupid Peter. Sorry. But it was a few days later that a little bit

01:28:06.580 more digging made me realize, uh, the FDA might be making a mistake here that we went and scrubbed

01:28:13.580 the medical reconciliations of all our patients, realized three of them took ranitidine. Luckily,

01:28:18.420 none of them regularly. We just called them immediately, said, stop taking this drug. Do

01:28:22.340 not pass go. Do not collect $200. Here's the drug you're going to take instead. Presumably anybody

01:28:27.200 listening to this, I'd feel pretty comfortable suggesting they do the same. What else is there to

01:28:31.580 do? What can citizens do beyond not taking this drug themselves and passing along that insight?

01:28:37.240 Is there anything that the citizens can do with respect to the FDA? I mean, how many citizens

01:28:41.100 petitions does the FDA get a year, by the way? Not sure what that exact number is. It's used for

01:28:46.300 such a variety of different things, but I think they get a few of them a week. But I assume that

01:28:50.960 they're all different, right? I mean, obviously they're all different. I guess what I'm saying is I

01:28:53.620 assume they're of different magnitude of importance. I mean, when a chemical lab of yours stature is

01:28:59.840 submitting this type of data, that's probably different than if I just rung up the FDA and

01:29:05.040 said, hey guys, I noticed when my patient took Crestor, it worked. And when he took resuvastatin,

01:29:09.940 it didn't. That's the type of citizens petition I assume that doesn't go too far. But do you have a

01:29:14.400 sense of how many citizens petitions of your nature and gravity hit their desk? I don't think very many.

01:29:20.560 Do you know how the FDA set the limit at 96 nanograms, by the way? Yeah. So the calculus behind that

01:29:27.320 is basically ensuring that there is less than one cancer case in 100,000 over the course of 70 years.

01:29:36.960 That's an extrapolation from an animal model, correct? Correct. So again, as a scientist,

01:29:41.600 it could be maybe it's not that bad or it could be worse. Humans are not the same as a mouse.

01:29:46.880 Well, David, is there anything else you want to say on this story? I mean, this is,

01:29:50.740 I got to be brutally honest with you. I was a little bit reluctant to speak with you

01:29:54.940 so early in the development of this story because I know that time always brings new insights. But at

01:30:03.700 the same time, I think truthfully, I felt a little bit, a sense of responsibility. I feel fortunate

01:30:08.740 that we have an audience now that is quite large. And if for no other reason than if this message gets

01:30:14.800 to a lot of people who then share it with a lot of people, it can make a difference in at least

01:30:19.780 some people's lives. And again, my calculation is on the asymmetric side of this, if this is wrong,

01:30:26.540 I still feel like we've done no harm in that, at least to a person, meaning we've harmed a company.

01:30:32.100 Let's be clear. If this is wrong, all the companies that make, who makes Zantac, by the way,

01:30:36.660 is it Sanofi? Sanofi bought the rights to in the United States. It's made by a whole bunch of

01:30:41.880 different companies. Right, right. So you've got all the generics and Sanofi that makes the branded,

01:30:45.720 et cetera. I mean, let's be honest. Let's look at it from their standpoint. They're being hurt by this.

01:30:49.780 If this turns out to be wrong, that's potentially devastating financially. I guess I am taking a

01:30:55.600 slightly different risk, which is that the risk of someone switching over to a different H2 blocker

01:31:01.000 or proton pump inhibitor is the worst thing that's going to happen. And the best thing that happens is

01:31:06.260 hopefully some cases of cancer could be averted over the next God knows how long. That might be

01:31:12.040 naive, but that's sort of the reason I wanted to talk with you. But I'm uneasy of the fact that there's

01:31:17.640 more questions than answers, too. One other thing, actually, that I think is important to underscore

01:31:22.540 here and could also play into this overall upside-downside calculus is that the reason this

01:31:30.460 whole issue came up again in the scientific literature in the early 2000s is concern over

01:31:36.360 water quality and NDMA in drinking water. And what we mentioned in the petition that is getting very

01:31:44.320 little attention, unfortunately, is that now that there's all this news and everybody's worried

01:31:50.560 about it for one reason or another of whatever the reading about Zantac and rinidine, if you're

01:31:57.000 throwing it away in the sink, down the toilet, even in trash, which goes to landfills and leachate

01:32:04.120 runoff from that can be treated in chemical methods. All of this is exactly what all these environmental

01:32:10.220 scientists for the last 17 years have been saying is a potential problem because it will form NDMA

01:32:16.080 in the wastewater treatment plant, which then gets used as drinking water. So we certainly feel that

01:32:22.980 if you're making the decision to no longer use a rinidine product, make sure you don't just throw it

01:32:29.740 away or certainly don't throw it down the sink or down the toilet. It needs to be disposed of properly.

01:32:36.640 I mean, essentially, it's got to be disposed of as toxic waste. It's got to be returned to the

01:32:41.700 pharmacy or to all these facilities that do medication disposal. Because another potential

01:32:48.200 downside of all of this is that everybody's dumping it and it's going into the water system

01:32:54.260 and then being converted to high levels of NDMA in drinking water. And now you have another potential

01:32:59.840 crisis. Well, that's a really good point. So again, just to make sure the listener understands

01:33:04.280 exactly what you're talking about. It's one thing to say, wow, this is an issue. I'm going to stop

01:33:08.460 taking my rinididine. But to flush it down the toilet or throw it in the garbage potentially

01:33:13.420 spreads the problem. Now, have you heard of pharmacies accepting samples back and doing

01:33:19.740 whatever is appropriate to dispose of it? I mean, from a practical standpoint, what could somebody do

01:33:24.060 the day they're hearing this? I think specifically, I believe it was Walmart or some of the big

01:33:29.740 pharmacy chains have said that they'll take your product back and even give you a refund.

01:33:35.620 I mean, I don't want to put words in their mouth, but it's something that pharmacies are set up to do

01:33:40.280 and quite sure that a number of them have gone out and said that you can even get a refund for this.

01:33:44.980 Well, David, this may not be the last time we speak because I suspect one, there'll be more to

01:33:49.440 this story, but I suspect that there may be other interesting health issues that crop up as a result of

01:33:55.980 your work. But again, I want to thank you for speaking on very short notice. I want to thank you

01:33:59.400 for speaking with me on a Saturday night. And more than all of that, of course, I want to thank you

01:34:04.640 for the public service that your company does to take care of a problem that honestly, a couple of

01:34:11.480 years ago, I thought was non-existent. And now between your work and certainly that of Catherine's,

01:34:17.140 I've come to really, really doubt the veracity of the FDA and in general, our regulatory environment.

01:34:24.260 I don't say that lightly. I certainly think the FDA is an amazing organization and I think we're

01:34:29.360 richer for it with respect to what most countries go through. I've met many people who work at the

01:34:34.440 FDA. There's great folks there. I want to be clear that I'm not disparaging the FDA, but there's

01:34:39.740 something fundamentally wrong with this type of decision-making. And I don't know where the buck

01:34:43.580 stops, but I'm definitely frustrated by this. And I want to make sure that people are at least

01:34:48.560 armed to make their own decisions, which may differ from mine and yours, but at least they're informed.

01:34:53.220 Absolutely. And I would totally echo that. There's tremendous good that comes out of the FDA and

01:34:58.220 tons of great people that work there. And I certainly hope that these kinds of scenarios will

01:35:04.560 at the very least bring more overall engagement on these issues. And I also not entirely sure what all

01:35:11.600 the decisions are being made here. And I wish that there would be faster action on this specific

01:35:17.520 ranitidine case, but we certainly hope to work with FDA and regulators as a whole on these real

01:35:24.760 problems. I think obviously we have to come to the grasp of the reality that there are problems in the

01:35:31.520 medication system and generics, potentially even brand and all sorts of holes that exist in how the

01:35:39.520 system is now for medications. And we want to be a part of that solution and work together to ensure that

01:35:47.880 every patient is getting a high quality medication.

01:35:52.000 Yeah. Well, thank you very much, David. I appreciate your time and look forward to seeing how this story unfolds.

01:35:57.300 Yeah. Thank you very much, Peter, as well for spending the time on your Saturday night.

01:36:00.720 Thank you very much, David.

01:36:30.720 All with the ID, Peter Atiyah, MD. But usually Twitter is the best way to reach me to share your

01:36:36.440 questions and comments. Now for the obligatory disclaimer, this podcast is for general informational

01:36:41.340 purposes only and does not constitute the practice of medicine, nursing, or other professional health

01:36:46.200 care services, including the giving of medical advice. And note, no doctor patient relationship is

01:36:51.800 formed. The use of this information and the materials linked to the podcast is at the user's own risk.

01:36:57.500 The content of this podcast is not intended to be a substitute for professional medical advice,

01:37:02.220 diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical

01:37:07.700 condition they have and should seek the assistance of their health care professionals for any such

01:37:12.260 conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of

01:37:18.260 my disclosures, the companies I invest in and or advise, please visit peteratiyahmd.com forward slash about.

The Peter Attia Drive - October 14, 2019

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

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