Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk, Episode 89 I'm your co host, Dr. Kane, and I'm Dr. Schuman, and unfortunately, we do not have Dr. Patel with us today, but we'd like to wish her congratulations on her new baby and her current maternity leave, so we're gonna miss her today, and hopefully she'll come back soon, yep, and hopefully we won't get into too much trouble in her absence. So today's topic is teaching old drugs new tricks dramatic drug price increases with the FDA unapproved drugs initiative. And really what we're talking about today is an initiative brought about in 2006 by the FDA, why it came out and how it's actually impacted both drug price increases, but also drug shortages as well. Speaker 1 01:10 Yeah, so it's a chance to really go back, I think, talk about some about our clinical practice right now, but really also going back and looking at an evaluation about where pharmacy has gone over the last few decades. And so again, be careful about leaving the two of us alone. I think we're kind of have a Bill and Ted moment here, as far as kind of getting looking at some some time machines moving back in the past and zipping back to the forward too. Dr. Sean Kane 01:32 So, Dr. Schuman, with your permission, I think that we should have our inaugural sound effect of the HelixTalk podcast, which would be a time machine sound. Let's do it now. This is, Speaker 1 01:42 this is a Pandora's Box. Though, if we open this box, we may not be able to close it, even when she gets back, so we better be careful. Dr. Sean Kane 01:47 Well, she left us alone, so that's her fault. Let's do it. Let's begin the time machine. So, Dr. Schuman, go back to 2009 we've set our way back machine to 2009 and you have a patient who is now filling a prescription for Colchicine at your pharmacy, at the VA, and what do you think is going to happen in 2009 as your patient is filling that Colchicine prescription? Speaker 1 02:13 Well, this is actually a scenario. I'm not at the VA, but in a retail pharmacy, when I was a student that this actually came up and you had patients coming in expecting that. You know, medication is dirt cheap. It's ancient. It's old. It's been around a while. Gonna come back in, pay a couple bucks for my month's supply of the medication, get it, swipe my card and go off the day and patients came in and surprised. Well, the cost has gone up, and it's not nine cents a tablet anymore. It's $4.85 a tablet. We're talking 50 fold increase. And let me tell you, I remember hearing some voices that were not too pleased within the pharmacy. You know what the world is going on. It literally was dirt cheap a month ago. What are you doing to me right now? Yeah. Dr. Sean Kane 02:51 And if you think about it like a patient really is not gonna have a good concept of why the again, 2006 FDA unapproved drugs initiative really impacted that 50x increase in their Colchicine prescription, right? Yeah. Speaker 1 03:04 And I think even if I had gone up to the window said, Well, you know, golly gee, Mr. Or Miss so and so, like, let me tell you what I learned in school about may not have helped as much. So, right? Kind of stayed on my side of the office that day. Dr. Sean Kane 03:14 So we're going to get into why that happened. But before we do that, I think we need to go back in our time machine to 2014 How does that sound? Unknown Speaker 03:21 I know I barely handle the last times jump. So let's see what happens. Dr. Sean Kane 03:28 So now it's 2014 and just like Dr. Schuman, you said that you had a personal experience with colchicine in 2009. I also had a personal experience in 2014 with a drug called vasopressin. So I was an ICU pharmacist. I personally, actually really preferred the use of vasopressin in a certain patient population in the ICU who have septic shock that are on high doses of vasopressors. So vasopressin is used as an adjunct for those patients in septic shock. And I was notified by our pharmacy buyer. Hey, by the way, the vasopressin that used to be dirt cheap, $4 a vial has been around forever, has now gone from $4 a vial up to $138 per vial, which represented a 30x multiple Speaker 1 04:11 increase in the price. Wow. Yeah, that is not a small amount, is it? No, it's not. Dr. Sean Kane 04:17 And again, this is an adjunct, so it's not an essential medication, but we really used a lot of it prior to that price increase. And again, the reason for that price increase was heavily influenced by this 2006 FDA unapproved drugs initiative that we're going to talk about a minute, right? Speaker 1 04:33 And so again, it's not to say that every single time a medication price increases, this is the reason why, but both Colchicine and vasopressin have that in common is that they are really examples of that 2006 FDA unapproved drug initiative. Dr. Sean Kane 04:46 Yeah. And of course, drug pricing is multifactorial. This is two examples of this one specific circumstance. You know, drug pricing has been in the news over the past several years for a variety of reasons, and this is one of the many reasons. That is important to talk about. Speaker 1 05:02 Yeah, so you know what they had this initiative kind of ended up doing was took these some medications that have been again, around for a while, pretty much, you know, wild west mentality, anyone can make it, and really said, no, no, now we're going to bring it back under a closer watch, only one manufacturer can make it, and therefore you get the same mark of exclusivity we talked about with patent medications, and as a result, again, even though we have decades of use of these medications, cost is going to go up as a result. Dr. Sean Kane 05:27 Now, to really fully appreciate why the FDA made this initiative in 2006 we have to go way, way back. We're talking back to law when you learned about pharmacy law in school, all the way back to 1906 so fasten your seat belt. Dr. Schuman, we're about ready to Unknown Speaker 05:44 go your rocky ride. Dr. Sean Kane 05:49 So we've gone all the way back to 1906 at the inception of the Federal Food and Drug Act. And basically this was an act that said, hey, anyone who wants to make a medication go crazy. But we have two rules for you. Rule number one is that you can't have an adulterated drug, and Rule number two is that you cannot have a misbranded drug. And that's all they cared about, right? Speaker 1 06:10 And so what this says is, this is the idea was, there was not a pre market approval. This is the idea of its retroactive once you're on the market, once you're out there, it's, it's up to the federal government to really to prove whether or not something's been adulterated or misbranded. But again, nothing's saying before you go on the market, you have to meet X or Y, so you want to sell cocaine, for example, which comes up sometimes in our clinic, go crazy, as long as it really contains cocaine and it's not adulterated and the label says that it contains cocaine. And there were plenty of products like that we talk about, sometimes in lectures, that cocaine has effects. It's maybe not the safest medication for chronic use, but it does have some pharmacologic effects. Didn't need to prove safety or efficacy at this time. Hey, does the box take up cocaine? Is there cocaine in it? Dr. Sean Kane 06:53 Cool? Yep. So really, again, all this 1906 act mandated was that the product was not adulterated, which meant that what was supposed to be in it was truly in it, in terms of, if it's cocaine, it's truly cocaine, versus something that was exposed to too much heat and no longer is cocaine. Speaker 1 07:11 Now, you know, when I think back to history of pharmacy, I know there's kind of when I think about this act, I know there was one kind of seminal moment that really made people aware of have some of the pitfalls of this mentality. Dr. Kane, can you tell me about it? Dr. Sean Kane 07:25 Yeah, so to tell you about that, Dr. Schuman, we have to go back machine and really, for, you know, several decades, we just had you can't be adulterated. You can't be misbranded. And people were happy with that. And it wasn't till 1937 because of a tragic event that people really started questioning. You know, do we want the FDA to do more than just make sure that drugs are not adulterated and not misbranded? So you ready to fasten your seat belt again? Speaker 1 07:52 I'm ready. I've got, I've got the side of the desk. I'm gripping it and white knuckling a bit. Let's go. Let's go. Dr. Sean Kane 08:00 So what happened in 1937 was the sulfanilamide tragedy. And basically this was an antibiotic called sulfanilamide that was used to treat infections, and it was available as tablet and a powder formulation. But southern states, and I don't know which ones in particular, but somewhere in the south, people said, Hey, we would love to have a liquid version, not just tablets and powders. Speaker 1 08:21 In response to that demand, there was a chemist who was technically a pharmacist, who used diethylene glycol as a solvent, potentially to really create a liquid version of it called sulfanilamide elixir. Dr. Sean Kane 08:33 Now, for the chemists out there, diethylene glycol is very similar to ethylene glycol, which is actually a common ingredient in most antifreezes that are currently in the market. So antifreeze is pretty bad for you. It's actually it can kill you if you ingest it. And at the time that chemist, that pharmacist, wasn't aware of that toxicity profile, all that chemist knew was that, hey, this solvent is really good about dissolving sulfanilamide and forming this really nice liquid, right? Speaker 1 09:00 So you're saying is, he had a product. You label the product correctly. You put it on the market, it's going to do exactly what we say. It's going to do. It's going to dissolve. We're going to take it and it's going to help for your infection. Dr. Sean Kane 09:11 Except what happened was more than 100 people died because they took this sulfanilamide elixir, and they literally got the equivalent of antifreeze poisoning. This was over more than 15 states. The manufacturer made 240 gallons of this stuff, and by the time that they kind of recognized it, fortunately, it was early on enough that they recognized this. This harm was happening. And of the 240 gallons that were produced, the FDA was actually able to recover 234 gallons of it, which is amazing given the time of, you know, 1937 there's no internet. There's, you know, everything's on paper, pretty impressive, right? Speaker 1 09:46 So this is, again, an example of the FDA responding pretty quickly, but again, saving some lives in the way they slip through. So there's a lot of credit there. And I think it got, you know, thinking, okay, still, you know, if we had some sort of guidance before. Hand again, maybe we can, you can make that avoid it from even occur in the first place. Dr. Sean Kane 10:04 Dr. Schuman, what is so interesting about this is, had they not called it an elixir, the FDA would have had no legal mandate to actually be able to pull that product off the market. The reason is that an elixir has to contain ethanol alcohol. Speaker 1 10:18 See what I thought? You know here elixir, I usually think again, it was required to be made by somebody named Merlin or in some sort of collagen. But you've corrected me. Thank you, exactly. Dr. Sean Kane 10:27 And again, if you go back to that 1906 Act, the FDA is in charge of making sure that products are not adulterated, which means that the ingredients aren't what they are intended to be or misbranded, meaning that the label says something that it doesn't actually have. And in this case, they were able to pull the sulfanilamide elixir off the market because it was misbranded. It was not truly an elixir, but it said it was an elixir. That's the only reason the FDA had any mandate in this horrible tragedy of more than 100 people dying. Since we're Speaker 1 10:55 in a time machine, it's kind of like about the pharmacy equivalent of Al Capone getting busted for tax Dr. Sean Kane 10:59 evasion, exactly. And you know, at the time when the 1906 Act came about, the thought process was, certainly no manufacturer is going to make an unsafe product because that wouldn't be good for business. But this is a really good example that it wasn't even intentional. Thing that happened, the chemist had no clue that this would be a toxic product. But had the FDA had some proactive or prospective safety analysis that would have been captured. And, you know, these 100 people would not have died from this tragedy, right? Speaker 1 11:27 So we've kind of decided that perhaps this retroactive way about, well, we're not going to get it until we prove something. You know, it's on the burden of the FDA to prove something's bad. We're going to go the flip side. What if we had a gatekeeping setting that something was required to be proven as appropriate before it can even enter the market. Dr. Sean Kane 11:43 So that's a great segue to our jump of only one year. So don't just hold on tight. We're going to go to 1938 so 1938 The Food Drug and Cosmetic Act was approved, and this was 100% in response to the sulfanilamide tragedy. Basically what the 1938 act mandated was that everyone who's making a drug has to submit a new drug application or an NDA. And we still use something similar to this NDA to this day to approve new drugs onto the market. And what they had to do was basically show that the drug was safe. And that was the role of that NDA, of course, they still had to not be adulterated, and they had to not be misbranded, but there was no mandate of proving efficacy, anything like that. So it's not adulterated, not misbranded, and it's a safe product for humans to take. Speaker 1 12:36 And students out there, this is this 1938 act. This is one thing. If you haven't right, you are guaranteed to have this as a test question at some point in your career. So for sure, you get an easy couple points right here, if you just Dr. Sean Kane 12:47 remember that one. Yep, this is definitely MPJ oriented material right now, in terms of these acts and how it's really changed, how drugs make it to the market, and what, what they have to prove, and at what times they had to approve that. Speaker 1 12:57 So, all right, so, so Dr, K, we've got this idea that we have, we don't have to show efficacy, but we do have to show some semblance of safety before coming to market. And I know, obviously we're at a different point now. So what happened in the meantime? Dr. Sean Kane 13:09 Yeah, so basically, since 1938 several decades passed, and everyone patted themselves on the shoulder saying, Wow, we've really avoided some of these tragedies that could have happened, because we're requiring safety at this point and what happened through a couple different things that are kind of beyond the scope of today's podcast, but through a number of events, it became clear that probably we want efficacy proof, not just safety proof. And if you'll join me in our time machine, again, I'm bracing myself going to 1962 so 1962 the Kefauver Harris amendment, also called the drug efficacy amendment, came into play. And basically this 1962 amendment said that all drugs have to prove efficacy, not just safety, so they still had to do both, but now efficacy was also a new bar that all manufacturers had to meet in order to have a new drug approved onto the market. Speaker 1 14:03 So Dr. Kane, though. So the big point so we have this kind of a new a new watershed moment there. So the big question, does that only apply to all medications moving forward, or what do we do about the existing medications? So what happened Dr. Sean Kane 14:15 was, between drugs that were 1938 to 1962 those drugs had to undergo a review process, sometimes called a desi review process, that was the drug efficacy study implementation, and that took, you know, many years to complete. That any drugs post 1962 when they submitted their NDA, they had to initially prove efficacy and safety, and then drugs that were really old prior to 1938 were actually grandfathered in. They didn't undergo this desi review process, and they it was assumed that they were effective enough if people were continuing to use them after being on the market for decades. So really, to put a number to it, roughly about 3,400 drugs were considered DESI drugs that were approved between 1938 and 1962 — and those drugs had to undergo this additional review process to prove efficacy over some period of time, because they were in this kind of period between proof of efficacy and safety. Speaker 1 15:10 But I think it's important to note that we talked already about the 1938 Food, Drug and Cosmetic Act — medications that were on the market before that date were essentially grandfathered and the DESI review didn't apply to those. Dr. Sean Kane 15:23 So those are our grandfather drugs. We allowed them to stay on the market without having additional proof. And of course, during this desi review process, if a drug was ever found to be not effective, which actually did happen, in many cases, those drugs were forced to be removed from the market, even if the manufacturer felt that there was good efficacy. It was up to that desert review process to decide yes or no, you can stay on the market or not. So it Speaker 1 15:46 kind of puts us at an interesting point then is so that feasibly, there are still medications that have kind of sneaked their way in through this, you know, prior to 1938 and so we may have within our midst these medications that really haven't had the eyes on them that a lot of our newer medications Dr. Sean Kane 16:01 do exactly. And the FDA estimates that about 2% of prescribed medications on the market are actually medications that are unapproved drugs. Speaker 1 16:09 Again, when you think about how many prescriptions are dispensed in this country, that 2% cannot be a small number, no. Dr. Sean Kane 16:16 I mean, that's definitely a relevant number. And of course, that means that these 2% of drugs may not have proven efficacy, may not have proven safety, and we haven't even talked about how the FDA has a mandate to basically review manufacturing practices for how a drug is made for every manufacturer. So maybe they're not manufacturing a given drug appropriately, or they have inactive ingredients like diethylene glycol that are not appropriate. That's all part of that FDA review process. And about 2% of the drugs in the market haven't gone through that review process. Speaker 1 16:47 Now, since we mentioned this 1938 as a cut up when I'm assuming then that all these medications that it's referring to, these unapproved drugs, are all pre 1938 right? Dr. Sean Kane 16:56 No, and that's actually the really interesting thing. So some, certainly some of these drugs were pre 1938 grandfathered in, and we just kind of leave them there. We are accepting that they are unapproved drugs. What's really interesting is that those Desi drugs, the 1938 to 1962 drugs, some of those, the Desi review process did mandate that they be removed from the market, but the manufacturers basically didn't comply with it. So they said, You know what, we forgot that you sent us a letter. We're just going to keep making the drug that is on the market here. So you couldn't berate them on Twitter. So what else are you going to do? Exactly, and in all fairness to the manufacturers, some of these manufacturers felt that they did truly have a grandfathered drug, but the FDA thought, because you changed, you know, an indication or a formulation or something that it used to be grandfathered, and now it's not anymore. So sometimes there is disagreement, and that has to go through litigation in order to solve that disagreement. And that's another reason why some of these drugs that 2% of the markets may still be unapproved drugs, right? Speaker 1 17:53 So we said 2% is not a small amount. Obviously, any listeners gonna know what's within that 2% any common medications, any things that we use routinely that are that may fall into that range 100% Dr. Sean Kane 18:04 so in the ICU, for example, all of the time we use 50% dextrose to treat hypoglycemia. So IV dextrose, that 50% dextrose, most of those preparations are unapproved to drugs, and that's in a code cart in every hospital in America, and a very commonly used medication, certainly. Speaker 1 18:20 And another interesting one, obviously, we talked about Colchicine as an example of 2% lidocaine injections. I know we use, again, obviously topicals for in our in our pain clinic, but as a local anesthetic, or even using when you're giving another injection of a painful medication, using a little bit of lidocaine with that for local anesthetic, yep, very surprising to see that one on the list. Dr. Sean Kane 18:39 And again, a lot of that comes from how old that drug is. So if that was a grandfathered status, it has never really needed to go through that approval process. Another great one is sublingual nitroglycerin. So before 2010 and nitroglycerin was actually targeted by this unapproved drugs initiative. Before 2010 about 80% of sublingual nitro on the market was an unapproved drug. What that means is that 20% of the manufactured products were actually approved by the FDA in terms of how they were manufactured, making sure that the FDA had reviewed those preparations, but 80% of them were not, meaning that some guy in lab somewhere just made some nitroglycerin and sold it, and that was okay, legit, exactly. And of course, we mentioned vasopressin prior to 2014 vasopressin was extensively used for septic shock and was an unapproved drug. It wasn't approved through that new drug application process. Speaker 1 19:31 So I think one important thing to note is, again, not to just delve into the fear mongering, but explain kind of what are some of the legitimate concerns with these unapproved medications. We said they may not meet some of those FDA standards now that we've set up through the years, you know, first looking at safety, then also adding in the idea about looking for efficacy. What are some other things we need to kind of be thinking about? Well, a Dr. Sean Kane 19:53 big deal, especially with like that sublingual nitroglycerin as an example, is the manufacturing process, and this is something that the FDA. Absolutely does review when they're evaluating a new drug application. So for example, the FDA wants to make sure that every sublingual nitroglycerin tablet that you make is consistent, that it truly has the amount of ingredients that you say it has, and that that process is good enough to make sure that consistency is there. You also want to make sure that the quality is there, so you don't want to have kind of inactive ingredients that aren't supposed to be in there, or the purity of the product is adequate for what you're saying. And granted, some of this goes under the the umbrella of adulterated or misbranded products, but some of it doesn't. And again, that manufacturing process is really important, right? Speaker 1 20:35 Because again, I think about something, you know, as a sublingual tablet, the idea about, you know, concern about the degradation is gonna be different than your average tablet. So making sure there's a standard there, so it's not something that's gonna sit in a bottle and degrade really, really rapidly, compared to another formula, which holds a better shelf Dr. Sean Kane 20:51 life, exactly, absolutely. And I mean, just to mention another thing, the actual label itself. So the thing that you put on the bottle, yes, we mentioned how you can't be misbranded. But there are standards in terms of how the label looks. So you need to have an NDC number, for example. You have to have the drug name on it, stuff like that. Speaker 1 21:09 Even the font sizes, if I remember right, are they're very specific as far as what the bolding or the rates. So you have certain things that need to be highlighted Dr. Sean Kane 21:16 compared to others Exactly. And all of this label needs to be approved by the FDA to make sure that it is appropriate, right? And if this is an unapproved drug, the FDA has never looked at the label to provide feedback in terms of what's appropriate in that right? Speaker 1 21:30 So again, I think we've definitely shown through a number of examples about where there's problems with this unapproved process and why there are some good things about the way the FDA takes any of that. Sometimes we talk about the FDA being a delay, but that's because of the importance of really making sure these things are all sussed out before, before coming to market. So what is the FDA done? Though? Like to address this moving forward? Yeah. Dr. Sean Kane 21:53 So clearly, there is this issue. It's a really a safety issue. So to really fully explain that, we're going to have to hop back in our time machine to now 2006 the whole purpose of today's podcast. So this really brings about the 2006 unapproved drugs initiative. And this was brought about by the FDA, and their goal was to basically review all drugs that were unapproved drugs in the market that 2% that we talked about. And during this review process. It was important for them to incentivize drug manufacturers to basically submit an NDA so they will, Speaker 1 22:26 yeah, this is a whole lot of paperwork. So yeah, what would you do as to manufacturers say, to make you go through all this time and cost about doing something when you're already making a profit? What would they do? What could they give? Dr. Sean Kane 22:37 Yeah? So basically they said, you know, manufacturers, if you do this NDA process and we approve it, hopefully you're submitting new data to improve efficacy and safety. And if you go through that process, go through the paperwork, we'll actually grant you exclusivity on the market. So not only will we go after manufacturers that the Desi review process tried to kick out of the market, in terms of, you know, there's some issue in terms of disagreement or just non compliance with the Desi review board action. But not only that, if there are other drugs in the market that are unapproved, and you are the only approved drug, will actually remove all those unapproved drugs from the market and give you exclusivity, because you went through this NDA process. Speaker 1 23:18 And that's fascinating, because, again, you you may have, literally, certainly, a handful or dozens of different products competing in a very, you know, niche market. Now we're saying you essentially have full exclusivity within that that, I think that would definitely get some people to buy Dr. Sean Kane 23:32 in absolutely, if we just use Colchicine as an example, let's say there are 10 manufacturers of Colchicine. If you're one of the 10, and you go through the NDA, and you get approved. The other nine have to stop making their Colchicine product, and you get at least three years of exclusivity just for your Colchicine product because you went through this initiative. Speaker 1 23:50 And so imagine it makes sense, but hundreds of unapproved drugs have been removed from the market by this route, either from not filling the data, or, again, others coming in and providing that first patent, that market exclusivity moving forward Absolutely. Dr. Sean Kane 24:04 So it would seem that this is a great initiative to get potentially dangerous drugs off the market, to encourage drugs to comply with, you know, the current standards of what we want drugs in the manufacturing process, to show from an evidence standpoint. So everyone theoretically would pat themselves on the back and say, good job. We've really done it. This sounds like a really good thing, but it's actually backfired in many cases. Speaker 1 24:26 And again, the one thing I think about it comes to mind is the idea about the drug shortages. You know, you imagine if you have, and these happen all the time for various reasons, but if you have 10 companies making something at high volumes, and all of a sudden, nine of them are pulled from the market, and you have, even if the one person has exclusivity, it's going to take time for them to start ramping up their production there. And so you're going to see things just just dropping off. They're no longer available, or others maybe not wanting to go through that arduous process. And then as instead they say, You know what we're out of, we're gonna focus on something else that's more cost Dr. Sean Kane 24:56 effective, yeah. And a great example of that is in 2009, Amphastar, which is a manufacturer of many of the syringes used in code carts — atropine, calcium chloride, dextrose 50%, epinephrine. They basically decided it's not worth it to us to go through the NDA process, so we're just going to not undergo that potential legal risk of making these products anymore, and then we're just going to back out of the market, and this actually caused a national shortage, because they were a huge manufacturer of many of these code cart products, and the other manufacturers didn't have enough time to ramp up their production. So yes, it's good to have this process, but it has to be done in a safe manner. Because if you think about it now, if you have an epinephrine shortage, now it's not safe, because now patients can't get epinephrine in emergent situations when they need it, right? Speaker 1 25:44 So there has to be, I think, some agreement is the timing of it to allow for the, you know, some course corrections is that we're going to be bringing these eight, you know, no longer be manufactured, however, to do in a way that says we're not literally going to drop 80% of the supply just just the snap of our fingers. Dr. Sean Kane 25:59 And, you know, we already covered drug cost. And it makes sense that if you have exclusivity to a product, that you're going to be able to go up on the cost basically as much as you want. We saw that with Colchicine. We saw that with vasopressin. This is kind of this like double edged sword problem, so you're trying to incentivize manufacturers to go through this arduous new drug application process, but in doing so that allows the manufacturers to crank up the cost if they want to right Speaker 1 26:25 again, because if we go back to this, we're assuming that it's going to, you know, from as you said, as you said before. We're assuming that nobody wants to make, you know, an unsafe product and similar also, which is true, but we're assuming here that nobody wants to realize that exclusivity can lead to there's no competitor so we can charge what we want. Dr. Sean Kane 26:41 Yeah, and you know, there have been review processes done, and we'll actually link this in the show notes. Gupta et al in 2017 actually did a review of all products that underwent this FDA unapproved drugs initiative, and from 2006 to 2015 the median increase in cost was about 37% which is actually not terrible, if you think about it, but there are some cases that had substantial increases, many of which we've already talked about. So Colchicine became Colcrys, the branded product, which went up about 50-fold in cost. Vasopressin had a new brand name called Vasostrict that went up by at least 30x and then neostigmine (Bloxiverz), the brand name went up 25x so there are specific products that have these substantial and dramatic price increases as a median. The price increase isn't terrible, but there are definitely some of these commonly used medications that have had these dramatic price increases that put strain on the healthcare system, put strain on a lot of different areas, not to mention stuff like P&T committees, where maybe they're going to reevaluate, when do we use vasopressin for septic shock, or when are we using neostigmine? And maybe they'll actually change their prescribing practices or their ordering practices because of that cost change. Speaker 1 27:55 Yeah, so and again, it's amazing how this occurs. So I think what we can do now is maybe take a step forward and look a little bit more detail. I think Colchicine seems a good place to start — Colcrys, because that's the one that said, I know, personally this happened right when I was in school, so I was kind of got to see front lines, what happened to it. But this, you know, this is a medication been around for well over 3000 years as plant extracts. It's been available as a drug of the United States since the 1800s Dr. Sean Kane 28:21 so this would definitely constitute that like grandfather dinosaur type drug. But this was a target of the unapproved drugs initiative, and in 2009 the NDA for Colchicine was approved under the brand name Colcrys. And that meant that in 2010 you know, several months later, all other Colchicine products were forced off the market, and the maker of Colcrys was given three years of exclusivity to the market, just for acute gout attacks for colchicine. Speaker 1 28:48 and so and in that process, the new the NDA, did add some good new information to use for guiding a new efficacy data, new safety data, drug and information, information that was not available. I know I benefited from this in our clinic for number of times we do use Colchicine and we're concerned about different populations and dosing and interactions with with statins, for example, or other medications. Dr. Sean Kane 29:08 And really, that was the intent, right? The the FDA unapproved drugs initiative wanted manufacturers to produce more evidence to help us understand the drug better, right? Speaker 1 29:17 Because, again, is when this, you know, in 1800s nobody was like, but will it interact with my simvastatin? Exactly? Dr. Sean Kane 29:24 So, you know, yes, there was some new data with Colchicine, but it really wasn't substantially new. So we had plenty of data on how to use it, plenty of data on how to dose it. The guidelines at the time were using basically the same dosing strategy that we're using today. So yes, a little bit of new evidence came about from Colchicine through this initiative, but it wasn't substantially different than what we already knew about the drug. And then if we just look at vasopressin as another example. So this was actually a pre-1938 drug, so this would have received grandfathered status because the FDA act of 1938 didn't exist yet. In September 2012 Par Pharmaceuticals submitted an NDA (new drug application) for this branded product called Vasostrict. And what's fascinating about this is the drug manufacturer did not conduct any new data, so no new efficacy data, drug interaction safety data at all. What they actually did was they just used data that was already present, most of which was actually sponsored data from the Australian Government through grants, so they didn't have to pay money to have new studies done. Speaker 1 30:30 That seems to kind of go against the whole point of what this was about. Am I missing something there? No. Dr. Sean Kane 30:35 So, you know, kudos to the drug manufacturer for recognizing a good opportunity. They didn't have to pour a lot of money in. Of course, they had to spend time and money to undergo the NDA, but they didn't have to do new studies to prove efficacy and safety. And if we go back to that review article I mentioned Gupta et al in 2017 during that time period, 90% of the drugs that were approved through this initiative, they already had adequate evidence supporting them in terms of literature, and 90% of the time this actually happened, there was no new data that supported a drug being approved to the market. They used older data that was already out there to conduct their new drug application. So again, September 2012 that's when the NDA was submitted. It was approved. November 2014 by the FDA, December 2014 all other vasopressin manufacturers were forced to stop making vasopressin by January of 2015 they got market exclusivity at that point, and the price per vial went from $4 a vial all the way up to $138 a vial, just like what we saw with Colchicine. Exclusivity equals price increase. Yeah, and that's Speaker 1 31:40 my concern a little bit, is, you know, that timeframe is very rapid. As I said, we literally, you know, you get it a month later. Boom, everyone else is gone, and you get a month heads up. So you say after, one month after it's approved, tell everyone else you got one month to comply. And again, the concern is, everyone else, you know, or that, I'm assuming, that Vasostrict itself, they're not able to ramp up production to match everybody else who's making it. So you could have at that period of time, at the beginning, Dr. Sean Kane 32:05 it's a little rough, yeah. What's even more interesting is that this three years is basically the absolute bare minimum that will happen from an exclusivity standpoint. There's all sorts of other fascinating games that dragon manufacturers will play to basically extend out their exclusivity on the market. So for example, an ANDA, which is an application for a generic version, to go to the market takes roughly 24 to 36 months for approval. So by virtue of that, manufacturers will get that extra time of exclusivity on the market, because it takes so long for that an ANDA to be processed through the FDA, right? Speaker 1 32:44 And so manufacturers can submit new patent claims for the NDA as well. And then those submitting an ANDA have to wait at least 30 months to permit litigation if it occurs. And so you can kind of, and they talk about, I know, within the current market, with approvals, you know that indication creep into where it kind of, you start almost comboing and moving on to more and more things you cover. And you can see you can kind of drag out that period a little bit longer. Dr. Sean Kane 33:06 Yeah, absolutely more things get really tricky is manufacturers can sometimes sign exclusivity deals with chemical companies really exactly. And what can happen is, basically they can sign an exclusivity to say, You know what maker of vasopressin only sell me vasopressin will sign a contract, and you agree to not give vasopressin to any other company, and this is actually true with vasopressin. So there's three chemical companies that make vasopressin, all three of them signed agreements with Vasostrict that they will have an exclusive relationship, which makes it really, really, really difficult for an ANDA to even come out, because they have to now identify a new company to make this product that, in turn, has to be evaluated by the FDA for their manufacturing practices. It just raises the bar. It makes it much more difficult to enter the market again. Speaker 1 33:52 There's some, some law of unintended consequences. There's something coming out here that maybe not ideal. Is the FDA doing anything at this point to say, all right, some of this, you guys aren't, aren't exactly, you know, you're doing the letter of the law, but the heart of it isn't exactly being met here. Dr. Sean Kane 34:06 Yeah. So the FDA recognizes that this isn't a perfect solution, keeping in mind that hundreds of drugs have been removed from the market that potentially were not safe, effective, or underwent appropriate manufacturing practices. So there are some wins here, and work fairly, but also unfairly, focusing on some of these niche cases that have really impacted consumers and healthcare providers. So with that in mind, the FDA has said that, you know, moving forward, they're trying to identify and focus on products that are blatantly unsafe, those that have really poor claims, like false claims, things like that. So they're trying to prioritize the process of this unapproved drugs initiative, and also they're revisiting how NDAs are approved. Speaker 1 34:46 Yeah, so an example is looking at expediting the process for branded drugs in which a generic doesn't exist and there really aren't any patents or exclusivities in place already, and then looking at expediting NDAs, I believe, for any generic drug until there are three approved generics for a branded product. So again, to hopefully help with some of that market and shortages, Dr. Sean Kane 35:06 exactly, you know, and reviewing this whole thing, which, in all fairness, I didn't have a full appreciation for, kind of at the end of this, I was really thinking to myself, like, how am I as a healthcare provider supposed to know that vasopressin at in 2011 was an unapproved drug, and in this process, there are really simple ways that you can evaluate whether X drug is an unapproved drug or a drug that has undergone a new drug application. Right at NDC, right? You can just look at an NDC. Unfortunately, no. So NDCs are not how you can identify a drug or not. An NDC is a National Drug Code, and it sounds like that would Speaker 1 35:44 be used as proof that a drug is FDA‑approved. Dr. Sean Kane 35:47 exactly, and that's not the case. So herbal products, for example, that are not FDA approved as medications, will receive an NDC but are not approved by the FDA. So how do we check them? So another common misconception is the presence of a package insert. You know, the manufacturer makes a package insert. It doesn't necessarily have to be reviewed and approved by the FDA if it's an unapproved drug. So NDC numbers package inserts can be misleading. Where they look like a drug, they taste like a drug, but they're not actually a drug. So the best way to check is actually using the FDA website, drugs at FDA, this has all drugs that have been approved to the market since 1938 so this is a really good place to start. Another place to start is the orange book. And the orange book, which is available online, doesn't necessarily include all of those pre 1938 grandfather drugs, or the Desi drugs, so pre 1962 but this is a second place that you can look so drugs that FDA is the best spot. Orange Book is another alternative, but it may not include all of the drugs in the market. Speaker 1 36:45 And then, all joking aside about Twitter previously, actually, the FDA does have a decent Twitter account where they actually keep up to date on things like recalls and notifications. So in all seriousness, they do a pretty good job of trying to provide up to date information in real time as changes occur. Dr. Sean Kane 37:00 Yeah, and you know, there are some other references and resources that we can use. So the NDC number, so you can actually go to the National Drug Code website, which is produced by the FDA, and they'll actually give you the marketing category name. It'll say it's unapproved. It has an NDA, an ANDA, or an OTC monograph, to give you a concept of whether it is over-the-counter or not. Basically, what is that label approved for, or is it completely unapproved? And then also daily med. So if you use daily med to look at package inserts, you should know that this includes both approved and unapproved drug labels. But for an unapproved drug label, the marketing status will indicate whether it's been approved by the FDA or not. So to kind of wrap things up and summarize, you know, over the past 100 plus years, the FDA has really evolved from just mandating that you don't have an adulterated and misbranded product, all the way to requiring safety and now to requiring efficacy. And that's kind of where we're at Speaker 1 37:53 today, right? So what that leaves us with is about 2% of medications in the US currently that are these unapproved medications, meaning that technically, they never got that FDA approval for both safety and efficacy that's now required for medications. Moving forward, these drugs have been targeted by the FDA. They have under this unapproved drugs initiative started in 2006 to either demonstrate evidence of efficacy and safety or really to to be removed from the market. Dr. Sean Kane 38:17 And really, through this initiative, some of these older drugs have received FDA approval, and unfortunately that sometimes can cause drug shortages or can cause some, sometimes very substantial price increases. But in all fairness to the FDA, sometimes this does lead to extra data, new evidence that helps support the use of that drug in clinical practice. Speaker 1 38:38 And moving forward, though, if you do really want to know if a medication does meet with or if it has been grandfathered in or not. You can look at drugs at FDA website. The presence of an NDC number, package insert or entry in daily med does not guarantee that a drug is FDA approved, although in daily Med, they will look on there, if you look at the marketing status, and it will give you a little bit of a heads up Dr. Sean Kane 38:59 there, absolutely. So with that, if you want to see some of our show notes, it's available at HelixTalk.com just go to the episode number 89 to review some of the references and show notes. We're also available at Twitter. At HelixTalk, we love the five star reviews and the emails with episode requests or topic requests. We really value that feedback a lot. With that, I'm Dr. Kane. Speaker 1 39:21 I'm Dr. Schuman, and I guess to switch it up from what Dr. Patel says, I'd say just thank you for taking this a time machine. Ride with us Dr. Sean Kane 39:27 today. We'll talk to you later. Narrator - Dr. Abel 39:29 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 39:40 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.