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. Narrator - ? 00:11 This podcast 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. Unknown Speaker 00:31 Welcome to HelixTalk episode, 173 I'm your co host, Dr. Kane, Dr. Khyati Patel 00:35 and I'm Dr. Patel, and the title of today's episode is balancing access and safety the FDA's prescription drug risk mitigation strategy. We shortly know this as REMS. We're gonna hope to cover in this episode, just definition of what rems is. Why do they exist? Some history and you know, the role of FDA in developing this program, administering this program, and some examples of rems. And you know, at the end of the day, how does it impact us, pharmacist and when we are practicing out there? Speaker 1 01:08 So Dr. Patel, as you mentioned, REM stands for risk evaluation and mitigation strategy, or strategies. So this is core part of the role of really, any healthcare provider, to understand that medications have risks associated with them, and then to mitigate or reduce the chances of those risks from happening. This is a formal program from the FDA to make sure that we're being good stewards of that risk for our patients, right? Dr. Khyati Patel 01:32 And it's part of their risk mitigation strategies. And if we kind of do a time travel of when FDA started this, one example is package insert. Package inserts are part of their risk mitigation strategy. Formally, the REMS program was established in 2007 but we have examples of how FDA used to do risk mitigation. So talk about the controlled substance act that rolled out in 1970 that's where the patient package inserts kind of came about, and that's where we see the list of, you know, all the safety information, what to do, what not to do, the Accutane, which is still a program that is ongoing, the I pledge program we're going to talk about that that was actually initially established in 1988 if you believe it, but it wasn't called I pledge at the time it was the Accutane Pregnancy Prevention Program. We also have Clozaril. Speaker 1 02:25 I'm familiar with that because sometimes we have patients that come into the hospital where we have to go through the program for Clozaril at the time was called No blood, no drug in 1990 and then also thalidomide, back in 1998 had an education and prescribing program as well. So this is not new in terms of the FDA having programs to mitigate risk, but it just wasn't called REMS at the time, because that didn't exist until 2007 right? Dr. Khyati Patel 02:50 And then fast forward from all of this. You remember Vioxx, that whole debacle, and FDA really got scrutinized for not keeping the manufactured and the drug safety in check. So in 2004 they rolled out the RiskMAP program. It stands for Risk Minimization Action Plan. If you compare this to the current rems, this was less stringent, less comprehensive. FDA didn't have as much authority to really make people comply with this risk minimization program. Some examples, again, include Accutane. I pledge tickets in tips program, track clear TAP program, some of these risk map programs eventually, when rems was implemented in 2007 were converted to rems. So there's about 16 drugs at the time that were risk map were converted to the REMS, and then came the Food and Drug Administration Amendment Act of 2007 and this was the act where FDA kind of sought more authority over their ability to administer the program to enforce some of these restrictions on different parties. Right? We're talking manufacturers, patients, providers, healthcare system, who either dispense the medication or administer the medication. But yeah, that all came about in 2007 Speaker 1 04:09 and kind of not surprisingly, this did require legislation for this whole thing to happen. As you mentioned, it wasn't like the FDA in 2007 just said, Hey, we're going to do this. They actually had to have legislation that got passed in Congress for this to actually be a thing. And obviously other things happen in that bill as well. But this was one of those components, Dr. Khyati Patel 04:27 yeah, and obviously, with the Vioxx issue back in the day, you know, FDA was really under that scrutiny. And even though risk map was developed, they didn't really have the ability to make people comply, right? It was kind of Losey goosey. And so FDA said, Yes, you know, in 2007 we need some authority. We need some more ability to enforce these requirements. And so, kind of going back, you know, FDA, as we know, is the Food and Drug Administration. Part of FDA is this group called CDER (Center for Drug Evaluation and Research); a subgroup of CDER is DRISK, the Division of Risk Management, and DRISK is what oversees the REMS program. And again, the authority to the FDA is so much that FDA can require drug manufacturers to provide clinical studies and data, and they can request implementation of rems at any point in time in the drug development process. So it could be the new drug application, it could be post marketing phase of a drug. FDA can at any point in time, by assessing the current safety issues, can say, hey, I want you guys to start developing REMS for this given drug. Speaker 1 05:37 So then in that case, if the FDA makes that determination, that says, hey, manufacturer, time to do a rems program on this particular drug. Because we're worried about safety. They give the manufacturer 120 days to figure out what their rems plan is going to be, and that manufacturer then has to submit a plan about their rems management to the FDA for their review. Yeah. Dr. Khyati Patel 05:58 And so this was 2007 when everything started. So just in a matter of four years, by 2011 there were 200 drugs on this list. Speaker 1 06:08 That is crazy to me, Dr. Patel, because remember, prior to this, we just had a handful of drugs that were part of RiskMAP program, and prior to that, just a small handful of drugs that had their own unique programs. And we went from handfuls to 200 that seems like a lot. Dr. Khyati Patel 06:23 Yeah, I think the pendulum went from not having the supervision to having too much supervision and restriction. And there was some growing criticism about how FDA is too restrictive. It limits the access of certain medications to the patient. I mean, this is coming from all different stakeholders, right? Patient patient advocacy groups got also involved in this. Healthcare providers wrote letters, did testimonies to FDA, and currently looking at 2023 the list is 65 drugs. Speaker 1 06:55 And you know, without really knowing the 65 drugs, offhand, that seems more reasonable than 200 but we'll definitely dive into some examples of why we still have rems for certain drugs later in the podcast. Dr. Khyati Patel 07:07 Yeah, and this list is fluid, and so as we will talk about, you know later, how FDA works around rems. They could decide to add drugs or they could decide to remove a drug under the REMS criteria. So in terms of Speaker 1 07:21 the actions that are part of the REMS management plan, can you walk us through, like, some of the decision points or rationale of what a rems management plan might look like? Dr. Khyati Patel 07:32 Yeah, and so, as we said earlier, this is part of risk benefit analysis and management strategy for FDA, and it really focuses on preventing, monitoring and managing a specific and single risk that is serious in nature. So you know, if you open up a package insert, you're going to find many Warnings and Precautions, many common side effects, uncommon, riskier side effects. Some drugs may even have more than one box warning. But what rems really is, is they're going after this one particular risk, and they only focus on that. So again, it's not meant to kind of all encompass one drugs, all different side effects. Speaker 1 08:12 Then that strategy is going to include two things, communication, so in terms of providing information or education to patients, to healthcare providers or prescribers and to pharmacists that are dispensing the medication, and then also clinical actions, which there are reinforcing actions to help mitigate that risk or reduce the frequency or severity of whatever side effect or adverse event that we're concerned about. Again, one specific thing for the REMS program, one side effect that we're concerned about, Dr. Khyati Patel 08:42 yeah, and we're going to talk about, you know, the three main components of rems that we get to see, but patient, provider and prescriber. That's one subgroup that this, you know, risk management strategies apply to, but it also applies to drug manufacturers. So as we discussed earlier, you know, FDA requires the drug manufacturers to come up with the program. The expectation is that they also promote this information. So a drug manufacturer may have a website that talks about rems requirement. If a drug requires special registry, then there will be a registry website that the manufacturer has to maintain. An example of that is I pledge, and then basically they're also responsible for collecting the data and providing this data to FDA for ongoing analysis. Speaker 1 09:29 Dr. Patel, I think it's really important to highlight that these programs are not run by the FDA. The FDA has oversight where they make sure that the programs have a good plan, but the actual like, implementation, execution, data collection, this is all done by the manufacturer, not the FDA. Dr. Khyati Patel 09:47 Yeah, that is a really important distinction point, and it's really not up to the drug manufacturer to decide analyze their own data and say, hey, you know, we don't see the risk anymore, so we're going to ask FDA to remove us from the REMS. Category, it really is decided at that risk agency of FDA, they take a look at the available data. And so talking about, you know, all this data, everybody's flowing this data to FDA, what does FDA do with the data? And so there is this continuous assessment of the drug safety. Typically, they have requirements to review this data at 18 months since the establishment of the program, and then three years and seven years after. But they can decide to do like an interim analysis per se early on. And as we discussed earlier, you know, the list was 200 back in the day. It came down to 65 now. And so the REMS program is very fluid. At any point in time, upon the assessment of the data, FDA can decide to change the compliance, to change the restrictions, maybe make it more restrictive, maybe the risk is heavy, or maybe they've realized that people are not following the steps they're supposed to follow, or they realize that the safety issue is not as serious as they thought it was going to be, and they probably will roll back some of the issues. They would also look at access issues and then make sure that you know the REMS requirements are not limiting patients getting the medications they need. And so that might be part of the reason that would consider to loosen up a little bit. Speaker 1 11:24 So Dr, tell earlier on you said that, especially when we had the RiskMAP program, it was somewhat loosey goosey in the sense of the FDA didn't have teeth in terms of forcing manufacturers to do certain things related to this risk mitigation strategy. But then in 2007 when rems came out, that was one of the components to put some teeth to it. So if a manufacturer doesn't do what they're supposed to do, they could get in trouble, right? Dr. Khyati Patel 11:49 Oh, yeah. Now FDA really has the authority to inspect the REMS and enforce the requirements. So give you an example failure to comply, and this can go to not just the drug manufacturers, to any parties who's supposed to follow the rules right if failure to comply can result into either product seizure, injunction or civil money penalties. In the subsection, I think it was chapter seven, they say penalties can range from $250,000 to a million dollar per violation and the whole proceeding, for legal proceeding, it can range anywhere from one to $10 million Speaker 1 12:27 that some teeth right there to make sure that pharmacies, patients, providers and manufacturers are doing what they're supposed to do again to mitigate the risk to our patients, right, right? Dr. Khyati Patel 12:38 And this is not just on paper. This actually happened. So Juxtapid is one of the anti‑lipid medications used for patients who have familial hyperlipidemia, and the manufacturers agree on and they fail to provide educational requirements for the healthcare providers to appropriately prescribe this drug to their patient. And they actually found out that FDA found out that they weren't doing it, and they ended up getting $7.2 million in charges. Speaker 1 13:10 Wow, definitely a way to keep everyone in line when you have teeth to enforce the rules, right? Yeah. So obviously different drugs have different rims programs associated with them, and each program might be a little bit different because we're concerned about different things. Maybe the concern is lower versus higher, and that would dictate the degree or the stringency of the monitoring. So what are some of the strategies or elements that a rems program can have, again, with the thought that some programs need to be more stringent versus less stringent, right? Dr. Khyati Patel 13:41 The three main strategies we have is as laid out in the REMS program, is Medication Guide, communication plan, or itasu, that stands for elements to assure safe use. Now, as you said, Dr. Kane, you know, the implementation of any of these components can depend on the drug's risk, and it doesn't have to be mutually exclusive. So certain drugs can have more than one of the elements applied to them, but breaking down the percentages, most of the drugs lie under the itasu element, which is the elements to assure safe use. This is where clinical action, registry, training, all of those things needs to occur, and very few programs are in the communication plan or medication guide specific requirement. Well, let's Speaker 1 14:31 talk about medication guide for a second. So you said very few. We're looking at two out of 65 so almost none, but still a component of rems. What is a medication guide, and what do you do with it? And how does that help? Dr. Khyati Patel 14:43 Yeah, so you work in a community pharmacy, you get a patient's, you know, prescription leaflet, and there prints a 15 page medication guide, and you're annoyed that the trees are being killed out there, right? You may see that medication guide dispensing is common for lot of medications that are not. Actually part of rems. And so that's an important distinction to make, that every medication that prints a medication guide, not necessarily, is under the REMS program. However, there are certain, like we said, Two out of 65 currently you must provide medication guide to the patient. Speaker 1 15:18 So Dr. Patel, could you give us a couple examples of medications that have med guides, either because of rems or they have med guides but not required by rems. Dr. Khyati Patel 15:28 So one example is Prolia. Prolia has another rems too, which is communication plan. But med guide is one of the REMS for Prolia, for example. Speaker 1 15:36 And what about drugs that might have med guides but they're not required by rems from that 2007 program. Dr. Khyati Patel 15:42 Yeah, so normally, like procreate and celecoxib, are you know, n said products could have med guides printing, but they're not under the FDA rems program, perfect. Speaker 1 15:53 So that covers our med guide. The second one you mentioned was a communication plan. Is this like a letter to a provider? How are they communicating something, and who are they communicating to? Dr. Khyati Patel 16:03 Yeah. So this is like that, you know, dear healthcare provider letters. We call them. These are generally for anybody who prescribes the drug, any anyone who administers the drug. So certain drugs are restricted to administration in a hospital or clinic setting. So for nurses and then pharmacists, if they're a part of that dispensing act, they will get these letters. Sometimes these letters are also sent to medical societies or practicing boards, and so they make sure those medical societies and practicing boards can remind their practitioners that they need to follow these rems requirements. So Dr Speaker 1 16:39 Patel, can you give us an example of when this letter would happen and what might be the contents of a letter. Dr. Khyati Patel 16:45 Yeah, so again, I'm gonna give pro Leah's example. This one has not only the med guide, but that communication plan as part of their rems program. This particular example includes information about medication safety that the drug provider or the prescriber needs to keep in mind, such as the hypocalcemia, the osteonecrosis of the jaw, or the atypical femur fractures, serious infection or DERM reactions, for example, perfect. Speaker 1 17:13 Then, as you mentioned, the vast, vast majority, like more than 90% of rems programs, use the itasu, as you said, so elements to assure safe use, which is actually kind of like an umbrella thing of potentially a lot of different things that manufacturers or providers might need to do in order to ensure safe use. So what are some examples of that? Dr. Khyati Patel 17:33 Yeah, and again, these steps are not mutually exclusive. So there could be combination of these steps. Again, it depends all on the drug safety issues. And so examples could be that the prescriber and the pharmacist need to certify and carry out certain activities before they can dispense or prescribe the medications. They may have to continue some sort of drug safety monitoring and report the results of the drug safety monitoring on a periodic basis. And additionally, it requires patients to also get enrolled into certain registry or monitoring systems, and they would also require patients to have some drug or lab monitoring done in order to remain on the medication. So I think all three parties basically are required to work with each other in order to make sure patient is able to take the medication. Speaker 1 18:21 Yeah, so really, there's a couple different stakeholders that have to do something or have roles as part of this rems process. Potentially, so if we think about the prescribers, it could be that they have to enroll and, you know, take some training and then show that they are competent to prescribe a certain medication. It could be that they need to counsel patients and provide certain documentation to the patient about a given side effect could be that they literally have to enroll the patient in a rems program, either by mailing something in, faxing it, more likely, a website or a call center. Then, of course, when they prescribe that medication, they have to continue monitoring so it could be documenting that they are monitoring whatever the thing is that we're concerned about, to ensure that the medication is safe for that patient. It could also be a lab thing, so obtaining a certain lab value at some scheduled interval, maybe even submitting that lab value on a website or something like that, to document that they're doing what they're supposed to do. Dr. Khyati Patel 19:20 And other things can include making sure they know the particular prescription prescribing requirement. And that could include, like, I can't prescribe more than 28 day supply. I can't include refills on it. You know, it can't be a verbal prescription that I can just call into the pharmacy. And all of these things are necessary, and providers may not be able to do a regular prescription. It might be like a form that needs to go into the registry, and then the registry system will deliver the prescription, quote, unquote, to the pharmacy that is contracted. Speaker 1 19:54 And as we mentioned earlier, there's this really careful balance that all rems programs have to have. Which is ensuring safety and mitigating risk, but at the same time not hindering access for medications, for providers and patients, that balance is actually really difficult, and obviously the degree of how much the provider or patient or pharmacy has to do is dependent on the severity of the risk and things like that. Dr. Khyati Patel 20:20 Yeah, and it's very interesting, if you read the FAQs for each of these stakeholders and their roles and responsibilities on the FDA site, there is a growing concern about clerical steps, and you know, the paperwork that there needs to be done in order to prescribe a drug. And the cute answer from FDA was, well, you can have a person that gets trained in doing all the paperwork, and so that person manages the entire paperwork aspect of the care. Speaker 1 20:48 And if you think about it, so let's go to Accutane with the I pledge program as an example. That's in place because people were harmed by taking Accutane when they got pregnant or didn't realize the severity of the risk of getting pregnant while in Accutane, that's a really big deal. So making it incredibly clear for everyone, patient and provider, that you can't get pregnant when you're taking this medication, that's why that rems program exists, and that documentation is part of the insurance that that's actually happening, right? Dr. Khyati Patel 21:19 And certain people remember the Thaler meat babies right back in the day, but we are far from that picture. And so right now, probably the concern is like, what's the big deal? You know, we haven't seen this, but back in the day, those side effects actually did Speaker 1 21:35 occur 100% so we talked about the prescribers, roles and responsibilities, the second stakeholder are pharmacies. What kind of thing does a pharmacy need to do besides dispense medication, right? Dr. Khyati Patel 21:48 So there comes the pharmacy certification. In rare cases, a pharmacist will also have to certify, but most of the time, this is kind of a pharmacy certification where pharmacist or pic needs to make sure that their staff is properly trained know how to execute and meet the requirements. They may have to create workflows just like you know the paperwork system in order to make sure the prescriptions are processed without any delays to the patient. This may include ordering medications from rems approved distributor or supplier, and making sure they're being mindful of the whole quantity and no refill aspect. And you know, you can't fill it earlier than seven day supply that is left. That's, you know, example of one of the restrictions on dispensing the medication, not only prescribing, Speaker 1 22:39 then also sometimes the pharmacy is responsible for making sure that the prescriber is in the system, in terms of that they are a certified prescriber for whatever the medication is. So the pharmacy is actually validating that that's the case, also making sure that the patient is actually enrolled in the program, if that's one of the components, and then also that whatever safety monitoring that is supposed to be done was actually done. So if a lab value has to be checked within the last 30 days, they might go onto a website and actually verify that the prescribers in there, the patient's in there, and the lab values in Dr. Khyati Patel 23:10 there, right? And these are applicable to some of the safe use conditions before they can dispense the medication. Example is pregnancy test. Obviously, the prescriber educates the patient about the risk, but then there's some mandatory counseling requirements for the pharmacist that goes along with the dispensing. So it's not just a you know med guide. Print out the med guide and say, Here, you know is your information. You have to actually document that you provided the education the pharmacies, you know, prescribers too, but pharmacies have to make sure they also comply with any rems audit. So these audits can be done by FDA, could be done by the manufacturers or independent third party if they've been hired to do so. Speaker 1 23:50 So Dr. Patel, one thing that comes to my mind is especially for a medication that has a lot of stuff for the pharmacy to do. So they have to certify themselves, they have to log into a website, they have to do a bunch of things at some point. I could see busy pharmacies having some pushback in terms of the amount of time to complete all of these requirements. Is it kind of worth it? Conversely, I can also see that this is part of the pharmacist's role. Like different meds take different amount of time to fill and make sure that they're being safely dispensed. So are there any issues with that in your in your view? Dr. Khyati Patel 24:26 Yeah, I think this is kind of getting controversial. Many specialty pharmacies have come out and said, Hey, we have the staff and the ability to follow all these restrictions and rules. And so give us the, you know, these rems medication. And I mean to be really honest, in the latter years, we have seen transitions of these heavily rems authorized medications to be processed from specialty pharmacies. But it goes back to what you said earlier. It takes away from patient who is been at that one local pharmacy for four. 1415, years now, because they are on this medication, they have to go to a specialty pharmacy and talk to somebody that they've never spoken before, right? So there is some disconnect. I know some those small pharmacies have fought with manufacturers and FDA to say, hey, continue the care. Don't break the continuity of the care. We will take care of it. But on the flip side, the drug manufacturers we just gave you an example of $7.2 million penalty, right? Maybe they don't want to deal with millions of pharmacies that are out there to make sure that they're following what they need to follow and comply with the REMS criteria, right? And so they may choose to deal with just certain pharmacies, and say, We're gonna contract with 100 pharmacies. These are specialty pharmacies, and there, that's where the patients can get the medication, because we know they're certified. We know their process is, you know, complying with all the requirements and things like that, and we won't see any gaps in compliance. Speaker 1 26:03 Of course, the other wrinkle there Dr. Patel, and we've mentioned drug access several times. You know, we live in the Chicago land area where there's a bunch of pharmacies all over the place, and maybe patient has to drive a little bit farther to get to a specialty pharmacy. But what about the patient who lives in a very rural area where they don't have a lot of pharmacies, especially specialty pharmacies. Potentially, this could be a barrier to med access for those patients that they must go to a certain kind of pharmacy versus the one that is next door to their house. Dr. Khyati Patel 26:33 Yeah, 100% and that's why, you know, there is no right or wrong answer here. FDA does want to make sure that these programs are not burdensome in terms of the access. And so you know, anybody who wants to voice their opinion or voice their concern, there's actually a portal on FDA is, you know, rems website that's linked to our show note. You can actually reach out to FDA and present your case. Speaker 1 26:58 So we've covered two of the stakeholders. The third one is the patient. And at this point, you know, there's a lot of stuff going on here, right? A lot of requirements, potentially, what on earth would a patient have to make sure that they do besides take the medication? Dr. Khyati Patel 27:10 Yeah, they have to make sure they provide all the information for them to be enrolled in the registry, so address, birth, date, all that information to the provider. They should also make sure they're complying with the monitoring. You know, some of these drugs require monitoring before prescription, monitoring few days after prescription, and then monitoring every time they get refills done or in between as well. And so they have to be up to doing this monitoring. Otherwise, they can't have access to the medications. Speaker 1 27:40 Sometimes they may even have to sign an agreement, a patient prescriber, agreement, to say that they're going to do those things. Obviously they're going to get enrolled. Dr. Khyati Patel 27:48 And they also have to make sure that they understand they might not be getting the medication from their trusted pharmacy around the corner, that they may have to go with the specialty pharmacy, or even certain medications are limited to administration in a doctor's office or an infusion center. Like a good example is lemtrata that only can be obtained at a an infusion center or a hospital. Speaker 1 28:10 Then we've kind of covered it already, but there are requirements for the final stakeholder, which is the manufacturer. So they are responsible for coming up with what does the REMS program look like, planning it, developing it, getting it approved by the FDA, actually executing it or implementing that plan, assessing it as it's going on, and potentially modifying rems as new data comes in, or they discover that it's working well or not working well, then they are responsible for communicating with the FDA to potentially review, modify whatever needs to happen with that rems program, but it always needs to go through the FDA for their review and approval, Dr. Khyati Patel 28:45 right and communication of any changes in the REMS program. They need to make sure all of those previous stakeholders are kept informed. Speaker 1 28:54 Well, actually, we've actually gone through some examples, but I think it's always nice to go through more specific examples of what a rems drug, and then what are some of the requirements from a rems perspective for that medication we've already mentioned, Accutane, or isotretinoin, why don't we start there in terms of, you know, back in the day, it had its I pledge program that wasn't part of rems and then it kind of moved into the REMS program once that 2007 legislation went through, Right? Dr. Khyati Patel 29:20 And so Accutane, as we know it, is prescribed, commonly for a severe form of acne when you have exhausted all the, you know, preliminary medication, therapies and stuff. And so let's talk about why there is rems right? As we talked about earlier, there could be many different side effects, many severe side effects, but this FDA rems program is for a singular serious concern. In this case, it's teratogenicity that comes from isotretinoids. Speaker 1 29:49 So from a rems perspective, to make sure that we mitigate the risk of someone becoming pregnant, taking the medication and then causing fetal harm, we have an tassu So this is where I. We have specific monitoring in place. From a prescriber perspective, the prescriber, in order to prescribe Accutane, they have to be certified, trained and registered, and they have to have pregnancy test monitoring before they begin the Accutane prescription for the patient during treatment, periodically, then when treatment is done, 30 days after treatment, which is also interesting, Dr. Khyati Patel 30:22 yeah, and they can't prescribe more than 30 days supply at a time. They have to make sure there are no refills. Each prescription issue will require them to sit down and counsel the patient. And if there is any pregnancies that occur for a patient who is on the treatment, they have to report Speaker 1 30:39 it to the REMS program. So in addition to pregnancy testing, lots of counseling, the patient that is filling Accutane will actually fill out and sign a contract, basically. And part of that contract says that they promise to take two forms of birth control, primary form and a secondary form. So an example would be an IUD or hormonal contraception plus a barrier method, like a condom as an example. So one of the reasons why a provider might be mandated to report pregnancy is that that would be a big deal if, despite promising to be on two birth control forms, someone actually still gets Dr. Khyati Patel 31:16 pregnant, right? And this requirement for dual contraception is in place one month before they start the treatment during the treatment, and then 30 days after so again, they have to make sure that all of this is done so somebody can't just walk in and start this medication like you would do for you know, common prescriptions otherwise. Speaker 1 31:36 So Dr. Patel that covers what the patient and the provider have to do as part of the REMS program for Accutane. What about pharmacies? What are their responsibilities? Dr. Khyati Patel 31:43 Yeah, so similarly, they also have to make sure pharmacies are trained. There is a certification registration. They have to also comply with those prescription requirements. You know, 30 day no refills. They have to make sure that they're not dispensing the medication after the date that is provided in the I pledge system, there is a period of time that is considered the reporting time in after that, the pharmacies have to obtain recertification for that prescription that the prescriber had given in order to dispense from that particular prescription. And again, this is a medication that's available through closed distribution. So they have to get it directly from the registered distributor. Speaker 1 32:25 And then before dispensing that prescription, they have to make sure, obviously, everyone's enrolled, the patient and the provider, and then that they have authorization to dispense as well. Yeah. Dr. Khyati Patel 32:34 So there's like, a code that comes through. They have to make sure they enter the code in the iPledge system, and then iPledge will say yes, bless you. Go ahead and give this prescription to the patient. Speaker 1 32:44 And you mentioned this is closed distribution, so instead of getting Accutane from Cardinal or McKesson or a typical distributor, they're not getting it that way, correct, right? Dr. Khyati Patel 32:54 It's a particular wholesaler that is certified again, to make sure that they are giving the medication tool needs certified pharmacy, so they have to do the task on their end to make sure this is not just going out to anybody. And they also have to get the prescription directly from the manufacturers. And any anything that's on the overage, they have to send it back to the I pledge program to the manufacturer. Speaker 1 33:18 So there's a lot going on here, which is actually part of the purpose of registration, training and certification, to make sure that as a provider or a pharmacy that you're following the rules, right? Because there are costs associated, fees associated with not following the rules, and the best way to make sure everyone knows the rules is to make sure that they go through training and get certified and things like that. Yeah. Okay. Dr. Patel, how about another example? Dr. Khyati Patel 33:43 Yeah, there is another one called Revlimid so lange lidamide. This one particularly, you won't see a lot of patients on it. It's an anti cancer drug. You see patients with multiple myeloma using it. The reason why rems are applied to this drug is also teratogenicity. There is additional box warning for neutropenia, thrombocytopenia and vte, but the REMS for this particular drug only is for the teratogenicity component. Speaker 1 34:11 And as we mentioned, this is very common, that even though drugs have lots of other problems associated with them or side effects, rems is almost always for one specific thing that we're trying to monitor for Yeah. So very similarly to Accutane with Revlimid, we have in itasu So prescribers have to be certified. They have to check pregnancy tests 10 to 14 days before and 24 hours before the first prescription every week for the first four weeks, and then every four weeks thereafter. Dr. Khyati Patel 34:39 Yeah, that's pretty specific and intense. They also have to make sure before the initial RX, as well as each renewal, they are sitting down the patient and counseling and documenting the counseling. There's also this 28 day quantity limitation, no no refills. You know, they can't just do this over the phone and then counseling includes, you know. Know fetal harm risk, making sure the patient will comply with this pregnancy monitoring that's required. And just like the Accutane barrier method of contraception, in addition to another, contraception is required, here Speaker 1 35:15 again, the patient has to be enrolled by the provider, and then any pregnancies that happen, which shouldn't happen because the patient's well informed and also taking likely two forms of contraception. If they do happen, that has to be reported as well. Yeah. Dr. Khyati Patel 35:29 And then on the pharmacy side, very similar to the Accutane program, pharmacies will have to certify. They have to order the medication through the manufacturer's rems program. Have to make sure the providers, as well as patients are registered again, make sure you know they're not giving more quantity than required. They can only dispense this drug when patient has no more than seven days supply left. So again, they have to really call the patient and confirm, hey, you know, we gave you this on this day you shouldn't have more than six pills left. Okay, you're okay to you know this is your window to do the refill. Once they get the authorization to dispense, they have to make sure they are either shipping out the medication or dispensing the medication within 24 hours. So there are very specific requirements here. Speaker 1 36:18 And if pregnancies happen and the pharmacy hears about it. They also have a reporting obligation through the REMS program. And then finally, for patients, they have to be trained, registered. Obviously, they're receiving counseling. They're going to monitor for being pregnant, so they're doing lots of pregnancy tests. They are responsible for having, typically, multiple forms of contraception. Then they are also required to report any pregnancies if they were to occur, Dr. Khyati Patel 36:43 yeah, because, let's be honest, sometimes the you know the pregnancy reporting, maybe patients will find out at home even prior to the provider will be doing the pregnancy test. Speaker 1 36:54 No, so, Dr. Patel, how about a third example, and this one's actually interesting, because this came up when I was on my API rotations back in 2010 2011 when I was at Eli Lilly, and the drug was Zyprexa Relprevv, or olanzapine long‑acting version of that. Yeah. Dr. Khyati Patel 37:10 And as we know, this one is used for antipsychotic reasons, the REMS reason here, it's pretty interesting. This drug has restrictions to be administered in the hospital setting only because there is this post injection delirium, or they call it the sedation syndrome, involved with it. And so not only they get the medication in a infusion clinic hospital setting, but patients should agree to be monitored for three hours after receiving the drug, they can't drive home. They have to make sure somebody is driving them home, and obviously, you know, they're not operating any heavy machinery and things like that. They have to assure that. Speaker 1 37:50 And you know, Zyprexa on its own, olanzapine is a sedating medication. But what was the surprise here is that this version was supposed to be a long acting version of Zyprexa, or olanzapine. And what they found was that when they gave it to patients, some portion of patients got sedated, way more than what you would expect from just olanzapine. And that's the intent of the REMS here, right? Dr. Khyati Patel 38:12 And as far as the REMS components are concerned, so patients should be provided the med guide. And then there is this itasoup component of that. So the healthcare facility that would administer the drug. So in this case, yes, prescriber, yes, the healthcare facility, and yes, the pharmacy. It's not an outpatient pharmacy, but it's going to be that inpatient pharmacy who prepares the medication for the patient. They will have to be trained, certified and Speaker 1 38:37 registered, and then, as part of that, they're going to have training videos on reconstitution and administration. The prescriber needs to obviously counsel the patient that this is a potential side effect, and that's why they're doing this rems program. And then the prescriber has to enroll the patient as well as part of that rems program, Dr. Khyati Patel 38:56 yeah, and they have to just, you know, patient and prescriber has to make sure that they're okay with this three hour post monitoring. So think about post observation needs, and, you know, staff that needs to be there, and then making sure a patient doesn't go home driving, right? They have somebody to pick them up. Speaker 1 39:12 And, you know, Dr. Patel again. The whole point of the REMS program is to make sure that everyone is on board, everyone understands this, whatever the risk is, and that they mitigate that risk. It's almost like a joke, right? That when you counsel a patient, they only take in a portion of the counseling that you provide to them in terms of you list three, four side effects, and you hope they remember a couple of those after the session. I guarantee you, every patient in these rems programs can teach you about whatever that side effect is that they're monitoring for, because I'm sure it's driven home so many times from so many different providers through the whole process, Dr. Khyati Patel 39:44 right, right? They're doing this in a day in a day out. It's a repetitive fashion. They're tired of it, but definitely they can teach you. Speaker 1 39:51 Well, let's wrap up today's episode. So as we mentioned, rems stands for risk evaluation and mitigation strategies. This came out in 2007 through ledge. Legislation. It's part of the FDA job to mitigate risk, to balance risk and the benefits of certain medications. Dr. Khyati Patel 40:08 Yeah, and the elements of rems may vary depending on the drug itself, but can commonly include things such as medication guide, communication plans and other elements to assure safe views, which are requirements and actions and steps taken by prescriber, patient and pharmacies, Speaker 1 40:27 and those actions from those different stakeholders can include training, registration, enrollment, safety monitoring, documentation or safety concerns, and then following the prescribing and dispensing regulations, which, for example, could be a closed distribution system where you can only get the med from a certain distributor right. Dr. Khyati Patel 40:46 And what does FDA do with this data? They capture and assess the data on a regular basis, and they will make the manufacturers who are rolling out these rems program to make changes in the program. In addition to that, FDA has the authority to enforce compliance, do audits and take any punitive actions against any non compliant parties. Perfect. Speaker 1 41:08 Well for the listener, if you would like to get show notes, we have them available on our website at HelixTalk.com and you can see a link there for the FDA rems website with a lot more information. We also love the five star reviews in iTunes or Apple podcasts or wherever you listen to us. So if you could please provide a five star review, we'd love that. And we also have a mailing list, so if you go to HelixTalk.com you can get an email whenever new episodes come out, and that email includes the Show Notes and references and things like that. So with that, I'm Dr. Kane Dr. Khyati Patel 41:38 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 41:43 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 - ? 41:54 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.