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Certainly the interaction between pharmacist and the patient really is a very important one and I think as pharmacists you have to be very careful and listen to your patients and try to determine what in fact the issues are. But I hope that presentations, like today for example, helps you to understand that there is a lot of confidence that you can place in the, what we call subsequent entry products, in Canada. In fact we would have to say that the rigour that is surrounding all of this is really of the highest order. It is rigour that in fact is similar in Canada as it is in Europe or the United States or Australia, and so on. So I think you need to somehow assure your patients, the first thing, that Canada only uses products or permits its products to be used in patients that are of the highest quality. Quality in terms of both safety and efficacy and that there is really nothing to fear. Maybe as an extension of this, sometimes patients are actually very resistant and I’m familiar with this kind of thing. Your own jurisdiction across Canada will determine exactly what you can and can’t do in some jurisdictions of course it is a requirement that you use the lowest price brand; whatever that brand happens to be - generic brand. So you are sometimes just simply forced into using the lowest price and you can explain that to your patient. In other places you may, in fact, have some latitude but there is always the possibility of paying. If the patient insists and you only get reimbursed for the lowest price then what’s the choice? If you’re on the side of the patient you can say, “I’m going to give it to you for free”. Well that rarely happens in the pharmacy world. What is more logical is you say, “I’m reimbursed so much, my choice is for you to actually pay the difference and I’ll be happy to provide it”. So, I hope I’ve answered the question. Choices are sometimes very limited. Sometimes it means the patient really needs to pay the difference.
I think that the simple answer is that Canada wants to assure the patients that, in fact, any, can I call them competitive second entry products, are the same. And what we mean by the same is that the patient can expect to receive the same benefit; that there would be no greater incidence of any untoward effects and that the quality is the same. In other words, the concept of sameness needs to be brought to the patient so that they understand that Canada does not have a government that is insensitive to the needs of the people.
I think that’s a very good question. It’s the kind of thing that would be normally asked and I think it flows from this idea that Michael Kennedy actually mentioned in the Canada AM interview, which is, that the originators actually do their trials ultimately on patients and the second entry products, or subsequent entry products, don’t need to do this. I think it’s really important for you to understand some things about what the heart of bioequivalence is about. See the heart is, to find out, is there anything that differentiates the two products? That’s important to understand because what we are really saying is, is there anything different between how much gets in or how fast it gets in. Those are the only two issues here. It’s not whether the drug works because you see if the concentrations are the same in the circulation, then, in fact, they have the same purchasing power. The circulation delivers the drugs to wherever they are going to go, whether it is the brain, whether it is an arm, somewhere, whatever; the circulation does that. So if the concentrations and the circulation are the same, we expect the same effect. We expect the same effect whether that is another batch from the originator, whether it is the other capsule, like in my celecoxib example, another capsule in my vile, we are expecting the same effect. Why do we expect that, well if the absorption, both the extent and rate, is the same, then we expect that, in fact, we get the same response. So what this thereby means, is that, in fact, if you are going to evaluate how fast and how much it gets in, you want to make sure that it’s a simple test. And the simple test includes a group that is as homogeneous as you can create them, because it is the homogeneous nature of individuals that allows you in fact to make that test. If you confuse it actually with disease, what really happens is you get such variability complicated by the disease that you don’t focus on the real question. The real question is, same amount get in, same speed. And so there’s a good reason why patients aren’t used and, in fact, may I say, that patients aren’t used in the majority of cases. There are some cases where, in fact, patients are used, for example, one could think of toxic drugs like in the anti-cancer world where, in fact, you may want to actually use patients and this is being done. So there are circumstances where it would encourage the use of patients, but it is actually rare.
I think it is very important to establish that relationship of trust between yourself as a pharmacist and your patient and I think you need to understand what is actually going on. I think, as we sometimes encounter with the use of medications and switching medications, there is more to the story than meets the eye, so you need to make sure that you understand your patient very well and the kinds of things that are actually encountered. I must underscore, we are not expecting any differences and, when it comes right down to it, I think this study that came right out of the Boston group is very illuminating. It tells us that if we understand what is actually going on you can’t tell the difference.
First of all the criteria applies to every, can I say, every subsequent entry product or manufacturer, so what one finds, generally speaking, that the point estimates, and I go back to some of the statistics that have been done and I just want to amplify on that a little bit, we were a little rushed. You see the point estimate, which is like the average, cannot be very different than one. The reason being, you’ll have to bear with me here, suppose this is one and this is one point two-five and this is point 8, you see if those averages don’t hang around one, the likelihood of, in fact, the product failing because of the ninety percent confidence interval is shifted too much, you would just not have bioequivalent products. So, somehow there is this idea out there that, in fact, these different generic products, when compared against a single reference can be all over the map and thereby the idea that the two generics can’t be interchangeable, it just doesn’t work like that. Because the bioequivalence limits are so tight when it comes right down to it, that you can’t be very far off, and you are not bioequivalent with the reference. So thereby, the bottom line is this, if you are generic and you’ve satisfied the bioequivalence criteria and another generic has satisfied them. We have every assurance that, in fact, those two generics are also interchangeable and in fact it is no different than asking the question, what assurance do we have that two batches from the originator are the same or different? It’s the same idea. There are such controls over what needs to be done in manufacturing, validation of all of those kinds of things, that ordinarily we feel very confident that batches from the same manufacturer, in fact, give us the same kind of an effect. We are confident. I’m sure if I asked each of you in the room, are you confident that if you get one batch from brand “x” and a little while later you get another batch, which you very often don’t even realize that you are getting, that you get the same kind of response. It’s the same kind of thing with bioequivalence, the limits are so tight, when it comes right down to it, that, in fact, you’ve got every assurance that it is the same.
You know biologics and vaccines are a coming thing. I’m not sure if you read popular magazines or journals like The Economist, or whatever, but it’s the coming thing. What might be a little different between biologics, whether they be vaccines or things that are like, let’s say human insulin or something like that, is that, in fact, the process of production seems to be tied to the product that is ultimately coming out of all that. In other words, the way some people say this is that the product is ‘defined by the process’. Now, this is creating all kinds of angst in a variety of people. Probably, certainly, generic companies that want to get into the business, in some cases the clinical world, is very concerned about many of these things because if the process of production defines the product, then how can any other company come along and, in fact, create the same thing, as we call it, in the world of small molecules that we’ve been discussing. What has emerged is something called bio-similarity and, in the time of President Obama’s tenure, he has finally said that the United States is going to adopt the concept of bio-similarity. And the reason for it is that biologics very often don’t have such strong links to affect that we might sometimes see of small molecules. There seems to be a fair bit of substantial variability and the current thinking is that if there is a certain sufficient similarity and, that’s to yet be defined, that, in fact, these products will be allowed to be out there as equivalent. But, time is still unfolding here as to exactly what these regulations will look like. Canada still does not have approvals in this particular area, but other countries do. Some of my work in other countries actually deals with this very topic. So, it’s coming. Do I believe you can create equivalent products in the area of biologics? Absolutely. Because if you can accept the fact that you are willing to have different batches or lots from the same manufacturer out there treating the same patient, you can do it with competitive products.
This afternoon as I was reflecting on what I was going to talk about here I was reminded of a book, in fact, I have two books by the author, his name is James Lynch. He was at the University of Maryland School of Medicine and has written a very fascinating set of books; one is called “The Language of the Heart” and the other one is called “The Broken Heart” and what he describes is the unbelievable affect, sort of predisposition, might have, on the way medications act. In fact, he does these terrific tests where he takes individuals who think they are absolutely resistant to public speaking and shows how, in fact, their heart actually exposes them. And, the same applies to the mind because the mind and the heart, and the mind is actually part of the engagement with the rest of the body, and so, what actually happens, I think sadly, is that people are being misled. Everything that we know about approved products in Canada is that they have met the most stringent requirements for equivalence. It doesn’t matter whether we’re dealing with the digoxin equivalent, warfarin equivalent or methamphetamine equivalent, very strong, very difficult criteria. I think the idea that it doesn’t work, that just doesn’t make any sense to me, absolutely no sense. I would want to explore, are there other criteria that are responsible for what is alleged to be a difference, but it can’t be the product. That’s my bottom line on that one. It can’t be the product.
I think the important thing to understand here is that the focus is on the drug, in other words, if, in fact, the excipients, the non-active ingredients, actually were important, than what we would expect is that they would modify or change what we see of the active ingredient in the circulation. And, the fact that they are bioequivalent, that the concentrations are, can we say, the same, tells us that, in fact, the non-active ingredients don’t have any role in it. And, lastly, I must say that, you know, I’ve walked the corridors of both, in some of my past responsibilities, corridors of both innovators and generic companies and one of the things I always looked at was, okay, so what are the ingredients you are actually using? You know what? You see ‘Redpath’ sugar. It doesn’t matter which one of the companies you are in. That’s what you see. You see methylcellulose from the same place because there are only limited places that actually produce this stuff. So, the idea that somehow we have, can I say, this sort of garage group of excipients and then sort of legitimate ones is bogus. It’s not the way it works. So, two things, they are absolutely reliable things and number two if, in fact, they had an effect you would expect to see it in the concentrations and you don’t see it.
I think what we are dealing with here, ultimately, is the issue of equivalence and there are some people that seem to be resistant to this idea of immunosuppressant switching. I’m not sure whether they have any legitimate reason to not use them. I know there is the feeling among some of the clinicians that there is a lot invested in the transplant. I completely agree. But, you know what, I think, generally speaking, when I look at the data that’s out there and what the criteria are for treating people, and I’m not talking just whether it’s a switching, it’s what is actually being used in treating people, and what are the criteria whether, in fact, the treatment is the right treatment. I’m surprised at how much variability there is out there in what is permitted and how often it’s standard doses and things like this. Folks, you can’t speak out of two sides of your mouth. If, in fact, you really feel that some of these things are essential and important there would have to be dosing criteria that are so rigid that very few clinicians would subscribe to them. And that’s the way it really works. And, so, do I believe you can actually interchange immunosuppressants? Absolutely. If you can interchange batches from the same manufacturer, you can interchange products from different manufacturers, as long as they are bioequivalent.