CHEM 125a: Freshman Organic Chemistry I

Lecture 30

 - Esomeprazole as an Example of Drug Testing and Usage


The chemical mode of action of omeprazole is expected to be insensitive to its stereochemistry, making clinical trials of the proposed virtues of a chiral switch crucial. Design of the clinical trials is discussed in the context of marketing. Otolaryngologist Dr. Dianne Duffey provides a clinician’s perspective on the testing and marketing of pharmaceuticals, on the FDA approval process, on clinical trial system, on off-label uses, and on individual and institutional responsibility for evaluating pharmaceuticals.

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Freshman Organic Chemistry I

CHEM 125a - Lecture 30 - Esomeprazole as an Example of Drug Testing and Usage

Chapter 1. Introduction: The Chemical Properties and Reactivity of Prilosec [00:00:00]

Professor Michael McBride: Okay, let’s start up. So remember we were talking about configuration, about handedness, which was introduced - the idea was introduced - in the context of a tetrahedral carbon. But you don’t need a tetrahedral carbon in order to have handedness. And an example is shown by the oxidation of a sulfide to a sulfoxide. So let’s first talk about the mechanism. What makes the sulfide reactive in this case? What do you see for an orbital that would make the compound on the top left? Russell?

Student: High HOMO.

Professor Michael McBride: Pardon me?

Student: High HOMO.

Professor Michael McBride: High HOMO, the unshared pair on sulfur. And how about the peroxy? Notice that’s not a normal benzoic acid. It’s got two oxygens in a row. What reactivity does that confer on it? Devin, you got an idea, two oxygens in a row? What’s going to be unusual in terms of an orbital? We’re looking, obviously, for a low LUMO.

Student: It’s probably going to be a higher HOMO.

Professor Michael McBride: Yeah, it’ll have — it has unshared pairs, no doubt. But we want it to react with the sulfur that has unshared pairs. So we’re looking for a low LUMO. Anybody got an idea? Russell?

Student: σ*, between —

Professor Michael McBride: σ* of the oxygens, because oxygen’s got a big nuclear charge, right? So its orbitals are low. Okay, so we have the unshared pair on sulfur, σ* on the oxygen, and we get one of these where we make a bond and break a bond at the same time, which puts on oxygen onto the sulfur. And notice that, as you said Devin, the oxygen has unshared pairs, the n electrons there. But those won’t give stabilization by mixing with an unshared pair on sulfur. But sulfur’s in the next row of the periodic table. So it has a vacant d orbital that can overlap with that. So you can get partial stabilization there, of the unshared pair on oxygen, which you could denote by drawing a double bond. Right? So we sometimes draw a double bond to sulfur. And we can lose the proton from that, and we get what’s called a sulfoxide. So there’s the mechanism of making a sulfoxide. And notice that it’s not planar at the sulfur. Even though the sulfur has only three substituents, it’s not planar. So it’s asymmetric. It’s handed, it’s chiral. Right? And obviously you could easily well have reacted the top unshared pair of the starting material, as well as the bottom one. So when you do the reaction you get a racemate, a 50:50 mixture of the sulfoxides. Okay, now we mentioned omeprazole last time. Here’s the chemical structure of omeprazole. What will make it reactive? Anybody got a hint for what might make it reactive? Elizabeth?

Student: A lone pair on nitrogen.

Professor Michael McBride: It’s got a lone pair on two nitrogens.

Student: Right.

Professor Michael McBride: Right? Okay. Now one way to discriminate between them is to protonate one of them. Right? Because when you do that, you now have this carbon-nitrogen double bond. Right? And the π* will be unusually low because of the positive charge that came from the proton. So acid is the stuff that’s going to activate this. So now you’ve got a low LUMO and also the high HOMO, from the other unshared pair on nitrogen. So bingo, you can add, just as the nitrogen would add to a C=O double bond, like that. Then you get this thing with now four bonds to that central carbon. Protonate again, and now this compound has two positive charges. That’s not so great, to have a dication. So you get rid of it. You can get rid of it by losing that original proton. But there’s another proton you can lose, just as easily, in this way. Right? So lose the proton on the nitrogen and then have those electrons re-form the double bond to carbon, and the electrons go out on sulfur, and you get this thing. Now, that happens — remember it’s the acid coming along; the H+is what caused this to happen to omeprazole. So if you have a pH, an acid pH between one and three, omeprazole will undergo this acid-catalyzed rearrangement, with a half-life of two minutes. So in no time at all it’s converted to this form, which is the active form. Now active to what? Well suppose you have an enzyme that has a sulfur on it, that’s got an unshared pair of electrons, that will make it reactive. What will make the drug, in this form, reactive? Anybody got an idea? Russell, I’m going to go to you again, because you answered the same question before. We just made this group here.

Student: Yes, that’s right.

Professor Michael McBride: What’s going to make it reactive?

Student: π* makes it —

Professor Michael McBride: Not π*, no.

Student: [Inaudible].

Professor Michael McBride: It’s the same as O-O, right? Sulfur is right below oxygen.

Student: I meant to say σ*,

Professor Michael McBride: Can you see that? So it’s σ*. Oh, that’s what you meant to say.

Student: Yeah.

Professor Michael McBride: σ* S-O. Okay, so we got that low LUMO and the high HOMO on the sulfur coming in. So we can do exactly the same reaction as before, right? Make a bond, break a bond. OH- goes away. Right? And we have this thing where we’ve now formed a covalent bond with the enzyme. So the enzyme can’t do its stuff anymore, right? Because it’s tied up. Okay? So the pump, the pump which takes acid that’s made in the cells that line the stomach and transports the acid into the stomach, doesn’t work anymore, because that enzyme is what did the trick. So the pump enzyme is inactivated and the flow of HCl to the stomach is stopped. Okay? And, in fact, this is an interesting problem in the design of the drug, because it’s acid that causes this to happen, in two minutes, to become the active form. But you don’t want it to happen until it gets into the cells that line the stomach. So you take the pill orally, it goes into the stomach. What problem are you suffering from, when you put the — when you take this pill?

Student: Acid.

Professor Michael McBride: Acid, in your stomach. So bingo, it’s going to happen in the stomach, not in the cells in the wall of the stomach. So they have to coat it with something that’ll make it get through the stomach first without doing its reaction, and so they say don’t grind the pill up — right? — before you take it. Let it get through. Then it gets through the liver, into the bloodstream, and comes back to the wall of these cells in the stomach, and then it gets activated by acid and does this trick and stops the acid from pumping into the stomach. So that’s the idea.

Chapter 2. The Economics of Clinical Trials [00:06:58]

Okay, now should a chiral switch, to a single enantiomer — omeprazole, Prilosec, is a racemate, it’s a 50:50 mixture of the enantiomers; enantiomers, remember, at sulfur, not at carbon. Okay? Now, if you go to a single enantiomer, will the drug be twice as good, or at least better? Can anybody see a problem that you would have? Right? When something interacts with an enzyme, the enzyme is a single hand. So the complex, the reacting complex, between the enzyme and the stuff that you’re reacting, is diastereomeric if that stuff is handed; if it’s right or left-handed. The enzyme say is all right-handed. So you have right-right, or right-left. One of them will be better than the other. Right? So is that going to be something that’ll be important here? If we make a single enantiomer of omeprazole — remember, we talked about thalidomide, ibuprofen before. Will a single enantiomer likely help? There’s an interesting observation about this compound, the active form, that makes it different from the original omeprazole. Do you see what it is? Incidentally, notice, that’s the original omeprazole. All that that mechanism I showed you did was to change that bond from there to there, and the proton from nitrogen to sulfur. Let’s go back again. That’s all that happened during the activation. But it did something crucial with respect to stereochemistry. How about that original form? Was it chiral?

Student: Yes.

Professor Michael McBride: Why? Angela? What made it chiral? Yeah?

Student: The bond is going — like it can either go inside or outside.

Professor Michael McBride: Right. The bond — the oxygen on the sulfur could be either going in or out; the sulfur is pyramidal. What happened when we activated it?

Student: It gets bigger.

Professor Michael McBride: Now it’s not chiral anymore. So this thing is not going to discriminate between anything, because it’s not chiral anymore. Okay? So this thing is achiral. Okay? So it shouldn’t make any difference which hand you’re using at this stage. Now, so there’s no difference after omeprazole has been activated by acid. Notice it’s not activated by an enzyme, because if it were activated by an enzyme, then it could discriminate between the two hands and one would be more activated than the other. Right? So that could be a difference. But that’s not true. It’s just acid that does the activation and makes it achiral. So at first glance one would think it’d make no difference at all. Still, it could be that one enantiomer is better at getting through the digestive system and getting back to the stomach, in order to do the trick. So it’s still possible. How could you tell whether it’s better or not? This is getting pretty complicated — right? — all the different things it would go through to get from here to there. How would you find out whether it’s worth using a single enantiomer? What would you do?

Student: Test it.

Professor Michael McBride: Test it. How?

Student: Clinical trial.

Professor Michael McBride: You’d do a clinical trial. Okay. So you need — but in order to do that, you need a single enantiomer in order to do the laboratory and the clinical testing. And we’re going to talk about that in just a second. But first let’s talk just a bit about the economics of this. These things called proton pump inhibitors are the newest generation of things to treat acid reflux. And here’s data from Wellmark, which is the Blue Cross/Blue Shield of Iowa and South Dakota; so a pretty small population area. And this is how many prescriptions they wrote for Prilosec in the period from 1999 to 2003; just went up by 250% to a quarter of a million. And if you go world — so 15% of the members of Wellmark got this stuff, as of 2003; and 600 million worldwide. That’s a big market. Right? So now here’s cost comparison for things that treat acid stomach. So the first stuff is Tums and Rolaids and so on. Those cost three or four cents apiece. Okay, then there are these over-the-counter H2 blockers, like Zantac, which are now very cheap; like thirty-seven cents. But they didn’t used to be, because they used to be covered by patent, and were prescription drugs. Okay. Then there are prescription versions you see of these H2 blockers, and Zantac, when it’s for prescription, costs $4.27 apiece.

Okay, but now these proton pump inhibitors come along. And in 1988 Prilosec came on the market at $4.61 a pop. You take one every day. Okay? But in 2002 the patent ran out. So now generic people started selling the generic version of omeprazole for $2.76, and AstraZeneca, the manufacturer of Prilosec, said we can do better than that; we’ve been making this stuff for years, so we’ll make an OTC version and have Proctor & Gamble sell it. And so in 2003 they introduced Prilosec OTC; which was actually exactly the same stuff but seventy-nine cents a pill. Right? But you can still get the prescription form, if you want the real thing, for $4.61 a pill. Okay, but so now you’re losing a big market. If your pills are costing only something like what?; 1/6th or 1/7th of what they originally cost.

So in 2000, AstraZeneca introduced Nexium, which is a single enantiomer. Okay? And now that’s $4.87 a pill. Right? And that process, to go from the R/S to the S, to go from the racemate to a single enantiomer, is called a “chiral switch”, in the industry; to go from a racemate to a single enantiomer. Okay. Now this was touted, within AstraZeneca, as the most successful U.S. launch ever. And here you can see the graph of how much better it is than Viagra, Vioxx, Lipitor, Celebrex and so on. Over this little more than three-year period it went up to eight billion dollars in sales. Okay? And you can see that there’s been a lot of integration of clinical and commercial enterprise at AstraZeneca. This is from a website that you can see there. In December 2003 they say:

“…the executive director and development brand leader” (at AstraZeneca) “adds the clinical and scientific proficiency as a research gastroenterologist. As Levine and his staff put together clinical development plans, such as additional indications or line extensions, they get commercial input at every stage.”

Well I don’t know if you noticed I drink water every once awhile because my mouth is dry. And just before — when I learned that the class was going to be filmed this year, I realized that I’d been suffering from hoarseness since last spring, and I figured that wouldn’t be good for the recording. So I went to see a doctor to find out if I could do anything about this, whether there was anything wrong. Now there’s something you can do for this, and Nexium has been the most intensively advertised stuff ever. Right? That was for the public. This is for doctors. Okay? So if you go to that website, you can see a seven-part, seven-scene description of why Nexium is so much better than anything else. And what I’d like you to do for a homework problem for Wednesday is to go through that show and evaluate whether this series shows that Nexium is superior or not. Is it worth paying five times as much for a pill, or six times as much for a pill?

Now, this is the FDA-approved label for Nexium. And so they did clinical trials, just as we said they should do. Okay, so here they tried to heal erosive esophagitis. So what they tested, you can see, is the healing rate for this condition, from 40 mg of Nexium, 20 mg of Nexium — so that’s the single enantiomer in two different doses — or the traditional omeprazole, the racemic stuff. So, “These were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies. The healing rates after 4 and 8 weeks were evaluated and shown in the table below.” Now suppose you were in charge of designing this test. How much of the racemate, omeprazole — so 40 mg and 20 mg of Nexium — but compared to omeprazole, how much would you have administered to compare with — so there are the single enantiomer, 40 mg or 20 mg. How much omeprazole would you use?

Student: Forty and twenty.

Professor Michael McBride: And why? Lucas, what do you say?

Student: 20 mg, as little as possible.

Professor Michael McBride: [laughs] Why?

Student: To show the best distinction between the new stuff and the old stuff.

Professor Michael McBride: Okay. Does everybody agree with Lucas? Kate, what would you choose?

Student: Well I’d want to do both twenty and forty. But it looks like there’s only one omeprazole.

Professor Michael McBride: Okay, but if you were designing the test, you’d do twenty and forty. We’ll have an auction here. Do I hear eighty from anyone? Rick you —

Student: I would do eighty and forty.

Professor Michael McBride: eighty and forty. Why?

Student: Because that way — because so omeprazole is a racemate. If you do eighty and forty of those, you would get forty and twenty of the active form.

Professor Michael McBride: Okay. Does everybody see what Rick’s saying? If you want the same amount of what is ostensibly the active stuff, you should have double the amount of omeprazole. Now this is what the label says, what was actually used; 20 mg. You win Lucas. Okay? Now why? It’s because that’s the approved dose for that disease. Right? That’s what the FDA approved, right? But we’ll give twice or four times as much of what we think to be the active ingredient to the other people in the test. Okay, so that’s the test. There were four different tests, and this shows it. But let’s summarize it with a graph that’ll show it I think more clearly.

So after four weeks and after eight weeks, these are what fraction of healing there was with the racemate, which is shown in open figures. And the shapes are different studies; remember, there were four different studies. And this is what you get if you use the single enantiomer, is 20 mg; which remember is twice the dose, if that one form is active. What would you conclude from this? Is it worth paying seven times as much, or six times as much?

Student: No.

Professor Michael McBride: Okay now — or you could use 40 mg. Now I think we would probably agree that it’s better, just eyeballing this thing, even if we aren’t statisticians. Okay? So four times the dose does a better job. Now, then this was heavily advertised. You may have seen these things for the purple pill. So you get this grey-haired guy here who says,

“If I told you prescription Nexium heals acid reflux damage better, you’d want proof. And now your doctor has that proof. Recent medical studies prove Nexium heals better than the other leading prescription medicine.” (Now notice, he says prescription medicine. The OTC stuff isn’t a prescription medicine. So this is a different test.) “No wonder they call Nexium the healing purple pill. So call your doctor today, because if left untreated the damage could get worse.”

So you can get a purple pill there. Okay, this is the test he was referring to, which compared esomeprazole, that’s Nexium, to lansoprazole. But again it’s 40 mg versus 30 mg. I don’t know anything about lansoprazole, but that’s what they tested anyhow. But notice incidentally, in the acknowledgements, this study was supported by a grant from AstraZeneca, Wayne, Pennsylvania. So these are not completely disinterested people, at least some of them, who are involved in this study. And it says, “So call your doctor today to learn about this.” And fortunately we have my doctor here, Dr. Duffey. So she’s going to give you her perspective [laughter] on Nexium and omeprazole. Thank you for coming.

Dr. Dianne Duffey: My pleasure Professor McBride. Thank you for having me.

[Technical adjustments]

Chapter 3. Duffey: How Do I Know that the Drug is Effective? [00:19:57]

Dr. Dianne Duffey: Well I can remember sitting in organic chemistry classe as a pre-med, wondering why it was I needed to learn how to make paint. So this is a real treat for me to be here today, to be able to talk to you about some clinical aspects of why it’s important to study and do well in Professor McBride’s class. Sorry. All right, so I’m a otolaryngologist, I’m an ear, nose and throat physician, and I work here at Yale. Some of you may recognize me from the health plan. And Professor McBride did give me permission today to talk a little bit about his case. So I’m not going to show you any confidential pictures, but I may allude to him here in the talk.

So first of all the disclosure. I don’t have any financial interest in any of the drugs or companies discussed today. I’m not on any speakers’ bureaus. So, in a word, I don’t really have a vested interest in anything shown here today. But I will discuss some off-label or experimental uses of these compounds. And the opinions presented by me are mine and no one else’s. So as you’ve heard testified here today, Professor McBride took Prilosec and actually did improve. So he sent me an email and was very excited that I could come and speak to you all today, and said, “By the way, my symptoms were improved.” So Prilosec fixes symptoms of GE reflux disease, gastroesophageal reflux disease, and laryngopharyngeal reflux disease, which is the entity that I treat. GE reflux disease is in the domain primarily of the gastroenterologist. So I’m going to refer mostly to LPR today, laryngopharyngeal reflux.

So we’ve heard that Prilosec works. Or does it? We really need to know. How is it we know these drugs work? Someone talked about clinical trials today, and I’m going to focus a little bit more closely on that, because that’s — we rely on these, and they come primarily from pharma. Yale University, my clinic, doesn’t really have the money to run extensive clinical trials on my patients. Sometimes some centers are able to do it, or you may have a grant to do something that looks at a drug. But primarily we’re relying on what the pharmaceutical companies tell us in terms of data. So about Prilosec working in him, all we know is that his symptoms are improved — they were in his body — eating his diet, and living his life, and taking the drug at the prescribed dose. But there are a lot of variables that we may not know about, and some of these variables are what the pharma companies need to take into account, when they’re doing these clinical trials, when they’re designing them. Are we taking other patient variables into account? For example, diet; does he take a large number of herbal supplements we don’t know about, for example? This could affect the pharmacodynamics. It could affect the pharmacokinetics of the drug in his body. Did he take the prescribed medication on an empty stomach, as it’s supposed to be taken, so that the acid will activate it early? In other words, was he compliant? And these are all things that I need to be taking into account when I prescribe a drug to a patient.

For example, these studies were done in patient populations, but they may have been done on the West Coast, they may have been done in China. Is that patient population representative of my patient population? So when they’re designing these trials, they try to control for as many patient individual variables as possible. In addition, these studies have to be statistically sound, because biostatistics drive these clinical trials and their design, so that if differences are actually observed between Prilosec and a placebo, or Prilosec versus esomeprazole, we have to be able to determine with reasonable certainty if these differences are real or if they’re due to just chance alone. So that’s where biostatistics comes in. And I submit — and I think Professor McBride, who helped write some of these slides, probably also feels — that there is some duty on the part, not only of the manufacturers, but of academic institutions, who are also running their own clinical trials, to actually design the studies so that it’s easy to understand; the data are there and they’re very clear, so that they can make also very legitimate head-to-head marketing comparisons between competitor compounds.

So I think this is very important. As a physician, I feel that I have a duty to really evaluate the literature critically. Sometimes I actually need to go back and pull the studies. I can look at the package insert, for these drugs, but how do I know — how can I actually believe it? So sometimes I actually go back and I’ll pull the study off PubMed, and read it. And we have to be able to ascertain the validity of the research that supports our choices as clinicians. There’s a lot of marketing out there; as we heard, there’s a lot of money to be made off these compounds. And I think I’m going to also propose today that we as a society, we as patients, we as members of the society, perhaps a society who may one day have a single-payer healthcare system, we need to be educated also. And this information’s available. It’s available on the web. You’ve already seen some of it from Professor McBride this morning. This website is a fantastic resource. If you have a question about any medication you’re taking, you want to look at the chemical compound of it, the chemical structure and how they designed it, how they make it, how it’s marketed, how it’s distributed, all this is available on the website. So you can just plug in the drug that you’re taking, or the drug of interest, and that information’s all there. It’s public domain. So use that as a resource.

But direct-to-patient marketing can be really effective. And this is also referred to as direct-to-consumer marketing. You saw some of it in the earlier slides, but all you have to do is turn on the evening news, and these ads are there, right? Every time there’s a commercial break, you see some happy person walking around, talking about this drug. And you just hear the drug name. You don’t hear anything more about it. You may not hear anything about the studies. But it can be very effective. So I think we need to look critically at some of the claims, and we need to think, is this really actually the right thing for me to be taking?

So my specialty — so back to our clinical model — my specialty is otolaryngology. I’m focusing on the larynx with laryngopharangeal reflux. The larynx is the voice box. It’s where your vocal cords are. It’s what we use when we’re speaking. Ear, nose and throat is another name for my specialty. But we’re talking about laryngopharangeal reflux, which is reflux, acid reflux, that primarily affects the voice box. It’s under-diagnosed. It’s also a significant source of morbidity and decreased quality of life — hoarseness, feeling like you have a frog in your throat, sore throat — and it’s frequently associated with other forms of reflux disease, like GE reflux disease, gastroesophageal reflux disease. So it’s a significant public health problem. And this is a very busy slide, but just to point out some statistics: that up to 10% of patients who present to the ENT practice, for any reason, may actually have symptoms or findings related to LPR, laryngopharyngeal reflux. It’s also increasingly recognized as a problem that can be associated with non-allergic asthma, and a great number of these patients also present with a history of acid reflux from other — where their symptoms are coming from other sources, such as the esophagus, for example. So reflux is a very big problem. I see a lot of patients. It’s estimated that up to 40% of the adult population in this country may have reflux; and some studies say even more. So there’s a lot of money to be made.

What is its treatment? In the year 2008, what we’re doing is we’re treating this with proton pump inhibitors. But I have to also put in a disclaimer that there was a recent meta-analysis, within the last couple of years, looking critically at the literature, and at a number of different studies. It evaluated about ten different studies, and there is also a significant placebo effect here. So the jury’s not completely out, but there are plenty of studies, in my literature, that support it to use for the treatment of LPR. I’m not going to go into all that today. But the reality is that PPIs are FDA approved. They’re out there. They’re easy to get. All you have to do practically is ask your physician for a prescription.

So what are we trying to target? Here is a reasonably good-looking larynx. So these are the vocal cords. This is the anterior portion. This is the posterior portion, back where your esophagus is, and there’s left and right. So this is what I see when I’m looking with a scope. I pass it very carefully through the nose and we get a very nice look at the larynx. And this is a patient with moderately severe laryngopharyngeal reflux. You can see that there’s a lot of swelling here, compared to these other pictures. This area back here is all beefed up, and this area down here also looks quite reddened. So this is what we’re treating with these proton pump inhibitors. And we’re hoping to take a patient that looks like this, and turn their larynx into something more that looks like this normal larynx. You can see the sharpened edges here. So data is out there. We can follow this clinically, and that’s usually what we do.

So another reality, when you’re considering these drugs that are being developed, as we’re hearing about today, and being prescribed, is that really only about one in a 1000 of these compounds that enter preclinical testing will actually make it to human testing, what we call clinical trials. And out of these only about a fifth may actually be deemed safe and effective enough by the FDA to gain FDA approval. FDA approval is the Holy Grail for a pharmaceutical company interested in developing drugs and getting these drugs on the market. Without FDA approval they can’t market the drug. Without FDA approval they can’t put out ads on the evening news. So this is an example of one of those documents that’s available on the website that I showed you. And this is the approval letter for Prilosec OTC, which came out in 2003. It was written to Proctor and Gamble by the FDA. And I just want to point out this area down here. This is an approval letter for this drug, given at this dose, used for this indication. So they’re very, very specific. The drug companies can’t — they’re not allowed to market its use for other indications. But this is really, really important information for the company in order to be able to put this out and actually start to see some return on their investment for research and development. So again I just want to point out, this is for omeprazole twenty mg, for the treatment of frequent heartburn.

Chapter 4. The Phases of Clinical Trials, Results for Esomeprazole and Omeprazole, and Off-Label Use [00:30:26]

Now here’s some information that — you saw a different form of this earlier. Esomeprazole also has approval by the FDA for a number of different indications, but also for the treatment of GE reflux disease. And what I want to point out here is that in the design of these clinical trials they look very carefully, strategically, at how can we show that our drug is better than the competitor’s? So clinical trials, when they’re designing these, are generally broken down into three phrases: phase I, II and III. We have phase IV, which usually occurs after the FDA has given approval for a compound. Phase I is used in healthy volunteers. The endpoint is really safety. They want to know what are the side-effects. Is this a drug that we can actually give to the public? And they also use a lot of studies to determine metabolism and excretion of the drug at this point in development. And these are usually smaller studies, and they usually only need anywhere from twenty to 100 patients for these. And then once they pass into phase I — oh sorry, let me say just a little bit about safety.

Some of the side-effects — in the industry they call these adverse events. This is a terminology that the FDA uses as well, and it really is just something to mean a side-effect. Somebody had something that was out of the ordinary and they happened to be taking the drug. So you have to at least consider that it may have been considered by the — it may have been caused by the drug. A serious adverse event would’ve led to some sort of damage to the patient, or extended care such as hospitalization or a surgery. And these AEs, adverse events, need to be reported to the FDA during the clinical trials. So they’re watched very carefully, and they can’t proceed through to the next phase of clinical studies if there are too many adverse events or, for example, if they have deaths; those usually tend to raise really big red flags. And again, all this information’s available on that FDA website. So if you want to see how a drug was developed and what adverse events occurred during its development, you can see that there, for the most part. There’s a lot of internal stuff that’s not going to be on there, but for the most part they have to report these AEs to the FDA as they’re going along.

In phase II they’re looking for effectiveness or efficacy. The preliminary data generated generally is for effectiveness of the compound for a particular disease or a condition. So this is where we start to get into specifics about which dose of omeprazole am I going to choose if I’m going to compare this to esomeprazole? They can compare it also to placebo. They can compare it to a different drug. And again they’re looking at adverse events, they’re looking at safety, but they’re also starting to now look, am I actually targeting the disease? The study sizes are usually bigger. And then finally, if it gets past phase II, you can get to phase III. And if anybody watches the stock market, looking at drug companies or biotech companies, phase III is where things really — you’ll hear about this. When Wall Street hears a whisper that a drug’s not going to make it through phase III studies, or it may not get FDA approval, you can tank the price of the stock. It’s really quite remarkable to watch, as a clinician. Because again I don’t really have any vested interest in any particular company, but I just find it fascinating that even just a suggestion will actually impact things economically, so importantly.

So here again we continue to look at safety and effectiveness. We may study different patient populations. They may look abroad to do some of these studies. India is a place where a lot of studies are being done these days - Eastern Europe as well. They may look at different dosages, and they may combine this with other drugs. These are usually very large studies. By this time they’ve gotten to — they want to see clinical differences that are so subtle that they have to have very large numbers of patients to make this statistically sound. So they cost — these studies cost millions and millions of dollars too. So these companies are very, very invested. They want to make sure that they get return on their investment.

And then phase IV occurs after the FDA has approved a drug. These are post-marketing study commitments, and these are commitments by the sponsor, the person actually doing the studies and marketing the drug and selling it, that they will provide additional information to the FDA about the product safety, efficacy or perhaps its optimal use. And more recently we’re hearing about phase zero trials in the cancer research literature — my area of research is in cancer — and phase zero trials are exploratory, first-in-human trials. So these are designed to speed up development of promising agents. As we know, cancer is a very big problem in this country, especially with the population aging, and it can kill very quickly. So these trials are designed to establish very early on whether an agent behaves in human subjects differently than it was expected from the pre-clinical studies. And that does happen sometimes. So you can imagine if you spent months and months planning a phase I trial, only to find out, when you put it into humans, that it reacts — it doesn’t behave the way you expected, based on how it looked in mice, you can lose a lot of money and you lose a lot of momentum. So these phase zero trials are being put more and more into play.

So back to our clinical model. So some of the studies that we already heard about from Professor McBride were to determine whether these drugs actually worked in patients with reflux or not. So, and I’m not showing all the studies, by the way. I just have to disclose that. I’m only showing you a few studies, just to demonstrate what type of data I have to actually take into consideration, as a clinician, when I’m looking critically at how the studies were done; whether I think the drug’s actually going to be helpful for my patient or not. So this was in a group of patients, a particular patient population, with already established erosive esophagitis; sounds pretty bad. It’s pretty uncomfortable. They studied these patients with esomeprazole and omeprazole, at similar doses, with similar numbers of patients in both arms. They found no statistically significant difference in the symptoms of heartburn, sustained resolution of heartburn symptoms in this group of patients. Now if you read the esomeprazole package insert, they state that they chose omeprazole twenty as the competitor dose, because it’s the FDA approved dose for this indication; which it is. So then I went to the Prilosec package insert to find that they did look at 40 mg when they were looking at these types of symptoms. They found that there was really no improve — no benefit to using the higher dose. So they went with the lower dose when they went for FDA approval. So that’s, I think, partly why they chose 20 mg.

And then also, if you look more closely, there’s also they lose some linearity between plasma concentration versus areas under the curve, which is plasma concentration in the patient over time. So it becomes less and less predictable, as you go up on the dose, how much drug is actually being seen physiologically for the patient. So once they get out of that predictable linearity, things become a little bit iffy, and you could potentially get into adverse effects. So I think that’s part of the logic for why they chose that. But again, I’m not trying to make an exhaustive argument for what should’ve been done or against what was done; just to give you some idea for what we have to deal with as clinicians.

So then finally these are some of the three studies that Professor McBride has already alluded to, showing that there are variable results. This one showed a definite statistically significant improvement in healing of erosive esophagitis for esomeprazole over — any dose of esomeprazole over omeprazole. But two other studies actually showed that there was no difference. So there’s another bigger study as well that’s not included here.

Professor Michael McBride: Actually it’s the next one.

Dr. Dianne Duffey: Oh I’m sorry, yeah there it is, okay. Yeah, so again you just kind of have to look at the literature and say okay, I’m convinced or I’m not convinced. I don’t know that there’s any right or wrong. But the FDA also has a role to play here, and they really vet these studies quite well, and they’re not allowed to market if they don’t feel that — if the FDA doesn’t feel that there’s sufficient evidence there to support it. So in my patient population, who have LPR, a large number of these patients have heartburn. They may or may not be treated for the heartburn already. I may be the first physician they see, and I may say, “Well do you also have heartburn symptoms?” Those would be GE reflux type of symptoms. So I can end up treating both of those if I put my patient on one of these PPIs for laryngopharyngeal reflux. So if I’ve just told you that these drugs are approved for a specific indication, maybe at a specific dose, how is it I’m able to use it for something that it’s not really even approved for? And this is where we get into off-label use of drugs.

So once a drug is approved by the FDA for any indication, I as a clinician can write it, as a prescription, for another indication. But the FDA has put out these guidelines, such that good medical practice and the best interests of the patient should prevail here, so that we’re using legally available drugs — it’s an important term — according to the — and devices — according to my best knowledge and judgment as a clinician. If we use a product for an indication that’s not in the approved labeling, I have the responsibility to be well-informed about the product, to base its use on firm scientific rationale, and on sound medical evidence. Now in my literature there’s a lot of sound medical evidence supporting the use for PPIs in laryngopharyngeal reflux. But I just also —

Professor Michael McBride: Can I ask you a question about that?

Dr. Dianne Duffey: Yeah.

Professor Michael McBride: You say you have a — it’s not underlined there but you say there’s a responsibility to maintain records of the product’s use and effects.

Dr. Dianne Duffey: Uh-hum.

Professor Michael McBride: Does anyone come around and collect those records and try to make something of them?

Dr. Dianne Duffey: I’ve never been contacted by anybody.

Professor Michael McBride: Are people pretty conscientious about doing that?

Dr. Dianne Duffey: I think that we’re conscientious about recording whether there’ve been side-effects at the given dose. We’re conscientious about recording whether there’s been improvement in the symptoms. But I don’t have a detailed questionnaire, in general. So —

Professor Michael McBride: Yeah. Because one would think that this would be sort of like a wiki, that even though you can’t afford to do a big study, that if you collect enough observations from enough people, you could make something out of it.

Dr. Dianne Duffey: We could, we could. But then you’re in to experimenting, if you’re doing it with the intention of actually showing or disproving a hypothesis.

Professor Michael McBride: Well but you said you have a responsibility to maintain the records. Why? [laughs]

Dr. Dianne Duffey: We do. No, I agree with that. I agree. But we’re not really obligated to submit it to an IRB. If we were doing it with the intention of definitely showing a difference one way or another, then that would be considered an experiment. So I would be obligated to run that through the institutional review board, which is there for the protection of human subjects, and to make sure that any studies that we’re designing are legitimate, that they’re ethical, that the patient has been given the opportunity to ask questions. They can refuse, they can drop out of the study. So, but they’re all important issues that I think would be in the realm of, at that point, doing actual experimentation. But it’s a really important — it’s an important point.

But we can use these drugs for off-label marketed uses. Now the drug companies importantly are not allowed to market; they’re not allowed to advertise for off-label uses of compounds. So again I have a duty, as a physician, to evaluate this literature critically and to really be able to validate or ascertain the validity of the research that supports my choices.

Chapter 5. Pharmaceutical Marketing Mentality and Q&A [00:42:01]

So just a very quick word about marketing. As I mentioned, my research area is in oncology. I’ve been involved in some clinical trials with oncologic drugs for head and neck cancer. And I get these emails all the time. Marketing is a really big deal when it comes to these compounds. Just to give you an idea, this one in particular is about how do you market your oncology products? And this is an actual meeting, to which I was invited. And one of the teasers here is that “in such a crowded and competitive market, the ability to differentiate your product has never been more important.” So this just gives you some idea of what the thought process is and what the general culture is. And this is again a wordy slide, but just to point out — and this comes from Nature News; it’s fairly recent — that industry is really starting shift attention now to other areas. So cardiovascular drugs, which cardiovascular disease is really the foremost killer in our country right now, but they’re really shifting their attention now to drugs where perhaps they can make another blockbuster drug; and that’s usually always what the impetus is, return on investment. So oncology drugs; immunology, which would be something for rheumatoid arthritis, for example; and neurology are going to be a very, very big focus of attention of pharma industry. So as you watch the evening news, or whichever channel you might be tuning into, you’ll be hearing a lot more about this, and I think a lot more direct to patient marketing is going to take place. So again, this has been a lot of fun for me to participate, and I thank Professor McBride also for stimulating me to think a little bit more deeply about proton pump inhibitors and how I use them.

Professor Michael McBride: Great. Thank you.


Professor Michael McBride: Leave it on, there might be some questions. Are there some questions for Dr. Duffey?

Dr. Dianne Duffey: I’d be happy to try to field any questions, as long as they’re not too hard. Yeah?

Student: I am an international student, and I have noticed in the marketing for drugs that they have on television here that they always give the full, like two paragraphs about the side-effects of the drugs, on television. Is that required, and why? How is that regulated?

Professor Michael McBride: Right, so the question is from — you said you’re an international student?

Student: Yeah.

Professor Michael McBride: She’s from Australia.

Student: I’m not used to that at all. So it’s sort of like whoa.

Dr. Dianne Duffey: Right. So she’s noted when these ads come on TV that there’s a very long disclaimer afterwards about the side-effects. And I’m not actually an expert on how the marketing of these drugs is done. I’m going to speculate here, but I’m pretty confident that this is correct, that the FDA mandates that they put that out there. So if you’re going to make a claim about a compound and how great it is, you also better tell the other side of the story. You better tell them, “Listen, we might fix your reflux but you’re going to get diarrhea.” You know? And it’s kind of funny actually, because if you look at these and you say, “Okay, I’m going to take that drug to fix my runny nose, but I’m going to get diarrhea and muscle pains and all these other things.” So it really — I think it’s probably mandated by the FDA, and the FCC also may have something to do with that. But that would be my speculation. Yes?

Professor Michael McBride: Sam?

Student: I was wondering what your opinion is about — I know recently one of the big things was like that Vioxx isn’t safe. Do you think that clinical trials, they should do longer term studies? Because I think — I don’t know of other specific examples, but a lot of drugs like it comes through after a long time, long-term use problems —

Dr. Dianne Duffey: Right, and then we wonder as consumers, is this safe? If I’m going to keep taking this drug for years and years, am I safe, or are my progeny going to be safe? It’s a good question. And that’s where some of these phase IV studies — they’re called post-marketing studies — come in. I was involved with one clinical trial where a phase IV study actually was mandated. And so for years afterwards that drug company had to continue to pour resources into contacting patients who had taken the drug — “Are you still taking it? If you’re still taking it, what side-effects are you having?” So those are mandated on some level. And the FDA really plays the key role there. And that’s been my experience. But it definitely raises questions. And the Vioxx trial just was devastating for Merck. And I think a lot — they didn’t see a lot of that coming. So I think for the pharma companies — correct me if I’m wrong; you may have more insights — it’s probably, it’s a decision that they have to weigh. How much resources are they going to continue to pour in? And that would, on paper, it would take away from their profits. So I’m sure there’s a lot of internal debate about it. But yeah, that’s where we’re thankful that we have the FDA looking out. A lot of countries don’t have an organization such as the FDA. You can market anything you want, for almost any indication, and whatever dose goes. So I think we’re very fortunate in that respect. I’m going to turn the mike over.

Professor Michael McBride: Well Dana’s got a question.

Dr. Dianne Duffey: Oh sorry, I’m sorry.

Student: I’ve heard there can be cases where a drug was actually more effective for a certain off-label use than the use that it’s actually FDA approved for, but it’s been FDA approved for something that has a bigger patient population, so you can potentially make more money. If off-label uses can’t be advertised, how do you as doctors find out about that and evaluate that?

Dr. Dianne Duffey: So the question is if an off-label use for a drug can’t be advertised by the company, how do I as a physician hear about it? I would hear about it from other clinical trials that were done, maybe have — may have been supported by the company; so as we saw an example of earlier. But I look for literature within my field. So laryngopharyngeal reflux is a perfect example of that. It works pretty well, for this drug, but you do have to take it for a longer time period, and sometimes you actually have to take it for higher doses than is recommended for GE reflux alone. But it works pretty well, and I hear patients all the time say that it works. I have other patients who say it doesn’t work. So yeah, we just have to look at our own literature. And there are smaller studies; they may have fifty, seventy patients. But in an academic institution, somebody who, with an interest in that particular area, may run their own study, because they want that information and the information’s not out there. So we look for good solid data to help guide our choices that way.

Professor Michael McBride: Kevin?

Student: As a physician, about off-label use, do you ever use drugs in an off-label use and take advantage of their side-effects, in that sense?

Dr. Dianne Duffey: Okay. I’ll give you — well yeah there was. So when — I don’t, I don’t really have any drugs that I use that for. But there’s one drug in my field; Botox, for example. Botox was being used to help weaken the vocal cords. Okay? It’s been used for that for years, in patients who have speech problems and don’t have good control over their vocal cords and the function. So you can use Botox injections. Then Botox injections came along for use in the face, and you read about this on page six all the time; it’s hilarious. But what they’ve also noticed was that migraine headaches got a lot better. So you can use that, you can use Botox to treat migraine headaches. And there actually are phase III trials going on right now by a colleague of mine down in Manhattan, looking at exactly that question. So yeah, you can use them for — and you can take advantage of some of these side-effects. But I don’t know of any specific negative side-effects that were used. But that just happened. You may see some beneficial positive side-effects that the pharma companies didn’t even know existed; they didn’t even target that. So we continue — so that’s where it’s important to do clinical trials, as a clinician. So I’m involved in clinical trials as well. And that’s sort of an ongoing duty I think, certainly being an academic institution, that we need to also play an important role. Okay? Thanks.

Professor Michael McBride: So if you have a few more questions, come on up.

Dr. Dianne Duffey: Yeah.

Professor Michael McBride: I’m sure you have to get back to your practice. But the time’s up now, and thanks again Dr. Duffey.

Dr. Dianne Duffey: My pleasure. Thank you.


[end of transcript]

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