Well, welcome, everyone. We're honored to be here with you today on World Schizophrenia Day. I'm Catherine Cook, a research associate professor from the University of Maryland School of Pharmacy, and I'm here with Dr. Megan Errett and Dr. Ray Love. And Dr. Errett, why don't you just share a little bit of background for the audience today? Thank you, Catherine. I'm Megan Errett. I'm a professor at the University of Maryland School of Pharmacy and have been working on this project in the REMS programs for quite a bit of time, looking at effects of REMS on access that we're going to talk about today, but also in advocacy in helping improve the REMS programs. Great. Thank you. Dr. Love? Yes, I'm a professor at the School of Pharmacy and in the Department of Psychiatry at the University of Maryland, and I've been working with REMS since they first came out for Clozapine in 2015, and Catherine and I had actually discussed doing this project several years ago and then were able to collaborate when we got an RFP from the Center for Excellence in Regulatory Research. Great. Thank you so much. Yeah, so our presentation today, it describes a collaborative project with the U.S. Food and Drug Administration, the FDA, and our goal was really to kind of understand the perspectives of healthcare providers who are using medications that have REMS risk evaluation and mitigation strategies for those medications, and specifically select psychiatric medications. So we're excited to share our findings with you today, but we also want to learn about your experiences with the REMS for psychiatric medications. So just acknowledging federal support, this project was funded 100% by the FDA. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement by FDA, HHS, or the U.S. government. So for today's presentation, I'm going to start, we're kind of tag teaming it up here, I'm going to start with a project overview, talk a little bit about the REMS program, the risk evaluation and mitigation strategies, just kind of as an overview, and then Megan's going to talk specifically about the REMS programs for the three medications that we're focused on, Esketamine, Olanzapine for extended release injectable suspension, and Clozapine. She's going to share the results and the findings from the focus groups of healthcare providers, and then Dr. Love is going to finish us out with some discussion and recommendations that came out of this work. So in terms of the project, the goal for this project was to provide recommendations for the REMS for specific psychiatric medications to improve patient access while ensuring safe medication use and limiting health professional impact. So I think the challenges for REMS, kind of the need for those is based on safety, but we want to ensure that it's ensuring appropriate patient access and not unnecessarily burdening health professionals. So that was kind of the overarching goal, is to provide recommendations. We did kind of four aspects to get to the recommendations, so we had a steering committee that guided the research. We convened a psychiatric medication working group to identify areas of concern regarding each of the REMS programs. We then held focus group interviews for each of the medications where we talked with healthcare providers on the elements to assure safe use, so the ETAZU, and then we summarized the findings for selected psychiatric medications. So on the next slide we can see a schematic of kind of how the differing groups worked together. So the steering committee was a five-member, really provided project oversight. They nominated and helped recruit members for the psychiatric medication working group and the participants for the focus groups. They also reviewed, commented on the interview guide, so the guide that we used to conduct the focus groups, they reviewed and commented on that, and then the final report for this project they also reviewed and commented on. So the psychiatric medication working group, it was a larger group, 12 members, and the reason for that was because we had at least three members that had experience using the medication and experience with the REMS for each one of those three medications, so Clozapine, Esketamine, and Olanzapine for extended release. So that psychiatric medication working group met, kind of talked about the challenges or concerns they had, which kind of helped inform questions that we wanted to ask the focus group participants, which were healthcare providers and professionals. And then that psychiatric medication working group also reviewed the results from the focus groups and discussed suggestions for improvements to the REMS program. And then you can see here each focus group, there was one focus group for each of the medications. They were separate. Individuals could not serve on more than one focus group, so if they were in the Clozapine they couldn't be in the Esketamine and vice versa. And we targeted six to nine members for each focus group, and they had to have experience using the specific psychiatric medication and experience with the REMS, signed informed consent because it was research, and then obviously participating in the focus group responding to questions that we had in the facilitator's guide. So just to kind of give a brief overview of the REMS, the FDA describes the REMS as a drug safety program that the FDA can require for medications with serious safety concerns to help ensure the benefits of that medication outweigh its risks. So the REMS are designed to help reduce, they don't always prevent the serious side effect, but they can reduce the occurrence or the severity of that said side effect by informing, educating, or supporting the execution of safe use conditions. And that's as described in the FDA approved prescribing information, the package insert or the label. The REMS focus on the preventing, the monitoring, or managing of that specific serious side effect. And so FDA actually is the entity that determines the need for whether that medication will have a REMS, but then the drug company is the responsible for developing the REMS program which the FDA reviews and then once it's approved then goes into existence. The REMS programs can be designed for a single drug or a class of drugs, and then each REMS has specific safety measures that are unique to either, unique to the safety risks associated with that drug or that class of drugs. So the elements to ensure safe use, these are kind of the required actions that the FDA can, you know, can I guess require for medical or educational interventions often by healthcare professionals prior to prescribing or dispensing the drug. So many of the REMS touch many different aspects in the healthcare kind of professional realm from the people, you know, physicians to nurses to pharmacists. But also some of these can affect the patient. The patient may have requirements in order to meet the safe use elements for the REMS. So depending on the risk, the REMS can have any or all of these six kind of overarching requirements. So it can require certification of healthcare professionals or specialized training can be required for anyone who prescribes the drug. Pharmacies may need to be certified or other dispensers. The dispensing administration may be limited to only certain settings or limited that you must have evidence of certain safe use conditions in order to dispense or administer the drug. And then patients may be subject to certain monitoring and then patients may also be required to be enrolled in treatment registries. So as of today, there are actually 63 REMS that are still in existence. Some of those are psychiatric medication. The FDA actually has a helpful public dashboard on their website where you can look at the requirements for the REMS, the elements. But our work focused kind of only on three of those REMS related to psychiatric medications. And so I'm going to turn it over to Megan to describe how we worked to understand the perspectives of the healthcare providers for those REMS. Thank you, Kathryn. Thank you. Okay, so we'll start with the discussion about the three products that we selected with the FDA to review in this particular product. So we started with esketamine, which the safety concern, as many of us are aware, is sedation, dissociation, abuse, and misuse. And then we have the REMS approval date and when it was last updated here on the slide as well. And all three of these did have an Etazu attached as well. The olanzapine for extended release injection has the post-injection delirium sedation syndrome that is required for the REMS. And then clozapine with the severe neutropenia. We wanted to be aware that the clozapine REMS that we used in this particular study was the one before the launch in November of 2021, which has been on hold essentially ever since. So we were looking at an older REMS, but a lot of our discussion could probably apply to the newer REMS that is in existence today. And we can have some discussion about that as well. So we'd like to spend a moment and think about some of the notable requirements if you aren't aware or haven't used these particular products, what some of the REMS requirements are. So for Spravato, this is only dispensed in healthcare settings administered to patients who are enrolled in the program, right? So the facility needs to enroll, they have to have a, I like to call them the champion. That's the person that sort of oversees the whole REM program and then each patient enrolls. And this is administered again by the patients under the direct supervision of the healthcare provider and the patients are monitored at this point for at least two hours after administration of Spravato. That's what's required in the REMS. The pharmacies that dispense this particular product must also be certified in REMS and only dispense Spravato to healthcare settings that are certified in the program. So it's not a patient takes it to their healthcare provider. This is a pharmacy is going to deliver this to a healthcare facility process. For Olanzapine for extended release injectable suspension, this is a very challenging medication to find anyone who is prescribing it. So you'll see from our numbers that we struggled a bit as well. In this particular program, the prescriber, the healthcare facility, the patient, and the pharmacy all have to be enrolled. The injections are administered at the registered healthcare facility. And this is exact wording from the REMS, with ready access to emergency response services. And we'll talk a little bit about in our focus groups what that might mean. But that's how it's explained. The patients are monitored continuously for at least three hours following the intermuscular injection. And then patients must be accompanied to their final destination after receiving the injection by someone else. So there is a lot of planning and participation in this particular program. For Clozapine, all healthcare providers who prescribe Clozapine must be certified within the program by enrolling and completing the training. Patients who receive Clozapine are enrolled in the program and comply with A&C testing and monitoring. Pharmacies that dispense are certified in the program by enrolling, completing the training, and only dispense to patients who are eligible to receive Clozapine. And just keep in mind, this was the older one prior to all of the dispense authorizations and all of the patient status forms and all of that, which we are living in now. So in order to start this project, we needed to elicit some healthcare provider perspectives on the REMS programs. We wanted to feel what is it like on the ground level in what I like to call the trenches, people that are doing the day-to-day work and where things are going. We want to investigate three different aspects within our program. We wanted to understand prescriber workload. So as a prescriber, what does it look like when you're having to implement these REMS programs and how does that work within your workflow? How does that work within your medical record and your charting and all of those particular aspects? We wanted to think about patient safety and are the REMS that are intended to prevent adverse reactions actually preventing those adverse reactions? And is it really the REMS itself in that particular process? And then patient access. Is there concerns about any potential inequity or denial of medication to patients because there is no access to these types of medications? And so many of the questions that we asked within this particular project could probably apply to any of the REMS medications. The three were selected because I think these are some of the more frequently thought about medications in psychiatry with REMS. As Catherine had mentioned, we created a facilitator's guide for our focus groups. And some of the potential questions that were written within this was how does the REMS impact patient safety, our ability as prescribers and providers to ensure that our patients are safe with the particular medications, how does the REMS impact patient access, and then workload? What aspects of implementing the REMS programs are manageable, you know, which are part of the normal process? And then maybe there are thoughts on where improvements could occur. Our project was occurring towards the tail end of the COVID pandemic, and so we thought about how does the COVID pandemic affect the use and monitoring of medications? In particular, it was notable for things like esketamine. If you couldn't come into a healthcare facility and have all those people in that space, I know that there were clinics that were delivering it to patients' home and the patient was standing on their house in a window and the provider was outside watching, right, because they have to monitor. So there was a lot of unique ways to think about how the pandemic was affecting this. Which REMS requirements are the most useful? And then ultimately, what suggestions did our focus group members have that can improve the REMS program? So our focus groups, as Catherine had mentioned, we tried to recruit between six and nine participants. If you aren't aware, the federal government has a paper load work burden that you can't have more than nine people in a focus group. So we were only allowed to recruit up to nine individuals in our focus groups. So we have here the sort of numbers of patients or a number of people that were in each focus group. For Clozapine, we had seven. For Olanzapine, we struggled to find our four. It is a very challenging struggle to find people that are actively engaged in this. And Spravato, we had six members. And then the dates of the focus groups are here as well. For our focus group participants, we wanted to make sure we had a diverse focus group because it not only affects potentially physicians or prescribers, but it also affects potentially nursing staff who may be administering meds, and then pharmacists on the dispensing side as well. We had an average of 9.5, 2.8, and 1.8 years of experience with Clozapine, the Olanzapine, and Esketamine. Many of them spent more than five hours per week providing REMS-related services. And when we think about prescriber time, there probably isn't a ton of administration time built into anyone's schedule. You're pretty much seeing patients on a routine basis. So that administration time, and then that's all tied up in REMS. If you get eight hours a week, five of it's tied up in REMS. That's a lot of time, not a lot of time for other duties. Many of the participants provided a wide range of services, prescribing, dispensing, administration, monitoring, education, just the program administration in and of itself, making sure all the forms are filled out, and then data entry as well. So a lot of aspects. So we'll go through each of the various programs here, and we'll highlight the positive aspects that were noted about each particular REMS, and then some suggestions for improvement. And then Dr. Love is going to come and have some further discussion and expound on some of these thoughts. So for the Clozapine, the positive aspects is we know agranulocytosis is a concern. It does need to be accurately monitored. Monitoring the ANC early in treatment is important to the providers. Monitoring leniency during COVID was very helpful. I think many people very much appreciated the ability to sort of bend and flex when labs and patients weren't comfortable with that. Designees reduce the healthcare professional workload and the ability to have someone complete your administrative tasks is helpful. And the bend diagnosis really improves patient access to care. Suggestions for improvements, reduce the amount of paperwork that goes into the Clozapine REMS. At this point now, we've probably increased our paperwork burden with the PSF and some of that. Reduce or suspend ANC monitoring based on duration of use, genetic markers, patient provider signed waiver, or allowable exceptions. Also to think about maybe longevity of treatment and what is the proper length of time that someone may need treatment. Provide guidance on identifying patients with BEN to make that a little easier for providers. During inpatient care, we definitely needed some thoughts on this as some of the changes about how many pills you can dispense when someone leaves and day supply. And then during inpatient, they're obviously being very closely monitored, so making sure that the relevance of the REMS matches with the level of care the patient's receiving. Making the website more user-friendly and enhance information technology. There's some thoughts about, you know, could this be just part of the electronic medical record if you have that accessibility. For the Olanzapine extended release injections, requirements for registration, access to emergency services and training aspects are fine. I think those are all very important that came out of the focus groups. Ensures prescribers and those administering understand the risks that there is with that post-injection delirium syndrome. Monitoring is important and affects patient safety. We do know that PDSS has occurred, so it is important that we are aware of how that occurs. Zyprexa relprev for this particular group was usually reserved for patients when nothing else worked due to the REMS that was required to do that. Swift resolution for website problems, they were very eager to help and able to reach people when calling the REMS program. So that REMS program was well-staffed and had plenty of people to help. Some suggestions for improvement, the REMS could just include registration, training and acknowledging ready access to emergency services, clarifying what that really means. So if you read the REMS, it will just say you have to have ready access to emergency services. People are very unclear. What does that mean? Does that mean I need to have a crash cart available? Does that mean I need to have a phone that I can dial 911? what exactly does that mean? When we were told by one focus group participant when they called to ask and inquire it said the ability to call 9-1-1 and be serviced by EMS. And I said well then that's what it should say in the REMS because I think that's very unclear. Reduce the amount of paperwork and make the website more user-friendly, which is beginning to be a theme for all of the REMS. For esketamine, the REMS are helpful for patient safety. Monitoring provides the accountability that providers may need to make sure that all of the monitoring is done. Hypertensive effects have been observed with the use of Spravato. Data collection is very useful for outcomes assessment, so they found that you know having that ability to monitor all that's helpful. Offering service still necessary during COVID, so being able to bend and flex. They aren't thrilled with the amount of paperwork. I think no one is thrilled with any paperwork that has to be completed. Facilitate registration. There was a lot of discussion very early on with esketamine and registration. Many providers don't work at just one site and so their DEA numbers are associated with one site that they work at. Your esketamine clinic may not be at that site, so when you register and if you have the esketamine site address, well that doesn't match your DEA address and so you couldn't register and it became this debacle of making sure that everybody's addresses matched up and I think that maybe that was an unseen situation when this was being created and discussed and it really affected a lot of provider workload in trying to make sure that addresses matched up. Eliminate documentation of vital signs and allow flexibility and post administration monitoring time. So if a patient didn't need to stay two hours that perhaps that could be adjusted. So overall the emergence themes that we saw was the value of REMS requirements on patient safety, the impact of registration process and REMS website on healthcare professional workload and making that an ease so that it was quicker and easier. Impact of monitoring requirements was individualized between patients. Impact of disparities provider availability and monitoring requirements on patient access. The impact of care transitions on patient access and healthcare professional workload is also challenging and we knew initially particularly with the close of pain REMS and transferring the patient to different providers can happen and the impact of COVID was definitely a theme that arose. So I'd like to turn it over to Dr. Love to expound on some of these themes and give us some discussion and thoughts or recommendations. Thank you Dr. Erd. So my job is to go into some of the recommendations of the report and that we did issue a report to the FDA and we have also submitted a lot of this excuse me material for publication so it should be available. So to kind of summarize a few points that that Megan made the focus groups were unanimous that the REMS were pretty effective in raising awareness of specific risks of the REMS medications but the REMS also had lots of unanticipated consequences and the primary consequences were the impact on providers in terms of workload and workflow and and filling out all of these forms and figuring out how to procure drug when DEA numbers didn't match up and all of those issues and and they also were fairly candid that these issues led to a hesitancy to use REMS drugs and REMS drugs in some cases now have a stigma about them because of the amount of work and each health care facility each prescriber each pharmacy that uses a REMS drug has to do a calculation can they afford to devote the resources to patients on these REMS drugs in order to comply with the REMS and what we don't know and what the FDA doesn't talk about is whether they thought about that when they implemented these REMS when these REMS were developed were they attempting to determine what these consequences could be and did that affect which specific provisions of the REMS were developed for instance in the Zyprexa relprev REMS was there any anticipation of whether this really would reduce cases of PDSS or how many cases of severe neutropenia would be prevented by the clozapine REMS or how much substance abuse was really being prevented by the Spravato REMS or how many dissociative episodes were prevented by the Spravato REMS we don't know what the FDA's thinking was on that and when you start having these resource issues again that is going to reduce patient access when there's hesitancy to use a REMS drug that reduces patient access I'm not going to go a lot into the specific recommendations for each drug because Megan covered a lot of that but there were some some common themes and the first theme was that with all the REMS transitions of care seemed to be difficult and and that popped up everywhere another theme that popped up was the REMS have very little capacity for individualizing care do we need to monitor everybody who gets Spravato for two hours or could that be less in some cases or do we need to monitor folks that get Zyprexa relprev for three hours could there be changes in the way that we determine who really needs ongoing monitoring of ANC for patients that are taking clozapine so this this inability to individualize was another theme Megan talked about the DEA issues and the interaction between the FDA and other agencies and developing REMS was also something that came up in the focus groups not only FDA and DEA but even CMS and payment issues we talked about the imprecision as another theme of FDA language we don't have any definition of benign ethnic neutropenia that's accepted for clozapine and Megan talked about the lack of definition for emergency services so we came up with some overarching recommendations in a bunch of different areas as a result of this and what happened was the focus group data was distilled by the investigators and the working group and the steering committee and people had input into what some of these recommendations should be the first recommendation was to talk about how to better justify the need for a REMS and the provisions of a REMS for the FDA to be transparent about what the outcomes of a REMS should be that there be evidence for any intervention that a REMS requires that before a REMS is implemented and after the REMS is implemented there be a mechanism for stakeholder input we know that a lot of the REMS did have stakeholder input when they were developed but frequently that was from high-level academicians it wasn't from community pharmacists it wasn't from community prescribers it wasn't from health care system administrators it was a bunch of academics that don't treat too many patients and if you're going to have a system that works then you need input from the people that are going to make that system work. The data from the REMS are not accessible for research we wanted to make sure that the FDA considered that external researchers need access to data and that that can positively influence the REMS. We wanted data on the performance of the REMS systems and we we asked the FDA to work with the manufacturers to make that available and there was a recommendation that there be an improved capacity to waive specific provisions of the REMS. There are some and we'll talk a little bit more about that. We talked about health care transitions already. Catherine mentioned that we have scores of drugs with REMS and every one of them works differently. You don't order the drugs the same way in any two REMS. The forms are not the same in any two REMS. The registration isn't the same. The education isn't the same. The websites aren't the same. Some don't even have websites. So there needs to be some standardization. If you're a provider who's using a couple of REMS drugs you've got to go into a totally different mindset every time you want to use that different drug. And God forbid that you're a pharmacy. If you're a pharmacy, particularly in a health care facility, you could have numerous drugs with REMS and nothing works the same for any of them. So harmonization was important. The processes needed to be consistent with provider workflow, not different from provider workflow or artificial as happened in some REMS. We talked about a single system for all the federal government agencies to deal with REMS. And then something that the FDA did a little bit with, but we haven't heard much lately about it, but they've said they do want to integrate REMS with standard EHR and pharmacy platforms, but that hasn't happened yet and we recommend that that needs to be a priority. That will help reduce provider workload. So let's start off talking about justification. We feel that if health care providers are going to have to implement a REMS, not only do we need to know the specific risks that are going to be mitigated, but we need to know how each element of the REMS, each specific provision, each thing that we're being asked to do, mitigates risk. It seems to many of the discussants in the focus groups that some of the, and I'll use a word that may be a little bit negative, some of the hoops that we jump through don't really mitigate risk. So we want to know how the FDA, at the beginning, feels like these are going to mitigate risk. We need some assurance that as we get experience with drugs with REMS, that that experience and changes in science result in changes in the REMS and that a REMS just doesn't sit there when it's no longer necessary or when specific provisions may not be necessary because now we understand the genomics or we understand other risk factors. And then we really want the FDA to set goals for what a REMS does, quantifiable goals. Everyone who works in health care has performance improvement systems and you're expected to reduce this by X percent. Well, if the FDA is saying that the REMS are to reduce risks, then we want to know how many episodes of PDSS we're going to prevent. What percentage are we going to reduce this by? What percentage of dissociative reactions are we going to reduce this by? So quantifiable outcomes are another element of justification. You know, anybody who pays attention when new drugs come out understands that the FDA doesn't approve a drug without substantial and significant evidence that the drug works. We want to know that the drug is efficacious. Yet, the FDA approves REMS with no data that any of the actions taken by the REMS are efficacious. We feel that if a health provider is going to have to implement provisions of a REMS, that those specific provisions or requirements or actions of the REMS should have some evidence to show that they're going to mitigate risk, that they're going to reduce the number of adverse reactions, that they're going to improve patient safety. So we would like the FDA to address the actions, the Etazu, as Catherine talked about, and say what's the evidence that these things really do reduce risks. I talked a minute ago about stakeholders and the need for stakeholder input, and I think where stakeholders can really give a lot of input is how to make systems less burdensome. What can we do to make this website work better? What's going to help the health care provider rather than inconvenience the health care provider? And finally, I think stakeholders can anticipate the unanticipatable consequences of a REMS much better than a drug company can, much better than the FDA can. So stakeholder review is something that we highly recommend the FDA consider doing much more of. I mentioned that we want REMS data to be available for external review. What we discovered was this is not built into the agreements between manufacturers and the FDA, and we recommend that it be built into these agreements, that the data must be available. And that data must not only be used to see whether the REMS is meeting its goals, but it can be used to see whether unanticipated consequences are developing, whether the program is affecting access to medication, are the barriers substantial or minimal, are the devoted resources to running the REMS adequate or not. So we want to have external reviewers be able to do that, not just the pharmaceutical company and not just the FDA, because they have vested stakes in the REMS. We also want and would recommend that waivers be reconsidered, and I'll give you one little case example here, and it's not from one of the REMS that we did in this study, but it's from the current Clozapine REMS. So those of you that use Clozapine know that we have this patient status form that needs to be completed, and there is a waiver that allows the pharmacist to dispense the medication without having that patient status form. But that waiver requires the pharmacist to have the patient's ANC. So a community pharmacy is going to have to have the patient's ANC, which they don't have, and that's what the waiver is. So the waiver really isn't a very practical waiver, and we think that when we look at these waivers we have to see how they can be made more realistic than what they are now. To kind of continue on the forms of REMS being more realistic, we don't believe that the FDA really considers the population impacted by the REMS as a person impacted by the REMS. And we know that folks with serious mental illness, that live with serious mental illness, they have very inconsistent living arrangements. They may end up in supervised housing. Then they may be homeless. They may end up in a correctional facility. They may end up in a community mental health facility. They can be anywhere, and it changes. And providers change. And they may move around. And because of this, the REMS has to consider that in the development. And so when stakeholders get involved in the development of the REMS, they can really talk about these things. And these are the issues that make transitions of care so much more difficult in the REMS. We talked about uniformity among REMS already. We talked about making REMS compatible with normal workflow. We talked about integration among federal agencies. And then we also noted that we would recommend an acceleration of integration with standard electronic health records and pharmacy systems. So to kind of conclude before we get to our questions and answers and conversation, the REMS are designed to improve patient safety. And most people feel that the awareness of patient safety issues has been increased by the REMS. Specifically, the focus groups did feel like the educational aspects of the REMS had some positive benefit, as Megan indicated. But other REMS requirements consume valuable resources. And they may actually alter therapeutic decision making because of this resource allocation, because of the burden on prescribers. And in some cases, the stigma that's been associated with a specific drug because of a complex REMS. We want to have one final statement to acknowledge that the REMS, as Catherine indicated, are a statutory requirement. There's a law that establishes the REMS. There's regulations that the FDA has to operate under. So the FDA can't change everything. And some of the recommendations we've made may be beyond their capacity to change. But there's a lot of the things we've recommended that they could change. And if the FDA can't change some things, the executive branch of government could change some things, because they control other agencies whose actions impact the way the REMS are implemented. And if the executive branch can't help us, Congress can change the law. So it really requires all of us, patients, advocates, health care providers, to keep an open dialogue with the FDA, with policymakers, with our elected representatives, in order to make changes in the REMS that will improve patient safety without compromising access and without burdening health care providers with excessive workload. Thank you. And I'm going to turn it back over to Catherine for questions and answers. Hopefully some answers. Thank you so much. Yeah, so I think now we'd like to, if anybody has any questions for us or if anybody would like to share their experiences with the REMS, don't be shy. Don't everyone rush to the microphone. We knew we could depend on you. I know. You know, I always say something. I swear it didn't occur to me until like halfway through your talk, I was in that focus group, wasn't I? Sorry. I do think the new Clozapine REMS is an improvement over the old one. There were definitely some, like, road bumps at the beginning, but having the opportunity to click the button that says, like, there's no lab because of extrinsic factors, which I've decided means, like, I just am not worried about it, has been a big improvement. And even just not having to put in the ANC, but to be able to indicate whether it's within range, like, really speeds up the whole process of doing it. One thing I was thinking about where you said one of the benefits is that it improves knowledge about the risks of certain meds. I was reading some records about a new patient that I got who was on Clozapine, and the person, the provider had written in their, like, discharge summary or something, like, patient was advised of the risks of Clozapine, most critically benign ethnic neutropenia, which is funny because I would not consider that being the highest risk of Clozapine. And so I actually wonder if, like, for Clozapine in particular, if it's actually sending the wrong message as if BEN is the biggest risk and not, like, acknowledging all of the other things that are probably more important to be monitored. No, I think that's a great point. I think in the focus groups we heard, you know, and even through the different groups, we heard concerns about other side effects that may be not brought to people's attention because you're so focused on one aspect. But I'll ask our mental health experts to talk about that as well. Yeah, I think that practitioners don't uniformly understand what benign ethnic neutropenia is and that the recognition of benign ethnic neutropenia in increases access and allows us to keep patients on medication who previously we could not keep on medication. And this is not a conclusion of the study, but this is my personal opinion now. I actually think that gastrointestinal toxicity is much more of an issue. And if the clozapine REMS focused on education rather than on ANCs, number one, we wouldn't have people considering benign ethnic neutropenia risk rather than a factor to be considered. But we would also be educating people on multiple risks because the FDA is not going to put in you have to submit every patient's bowel movement to a national registry or monitoring system. So I really think that going to this more educational realm, because you brought up the educational part, really could be beneficial. I think the education that occurs now is in some cases kind of minimal because with clozapine, for instance, you go in and you take the quiz over and over until you get all the right answers. I mean, how much does that show understanding? So I think we need to reconsider approaches. And I think if there were a more evidence-based educational approach, that would address things like you raised, issues that you raised. And I also wonder, you know, you brought up kind of the new clozapine REMS, right? And so I know our study kind of when we did the study, it was based on the old clozapine REMS. So I don't know if our experts have any additional information on kind of the new clozapine REMS and thoughts about that. I'll make a few comments and I'll let Megan chime in. But I think a lot of the issues are the same. You still don't do things in your normal workflow. In some ways it's worse because you may be putting in data, you know, from five weeks ago when it's not actionable. What sense does that make? There are some advantages like Dr. Richardson cited being able to push a button to waive certain blood test requirements, but then it still comes back to haunt the pharmacist. There were added provisions or provisions that were not really enforced before that are in the new REMS that were not in the previous REMS. So I think all of those are still issues with not just the new clozapine REMS, but all the REMS. It just isn't easy for a patient to undergo a transition of care. And if you think about it, our REMS are not patient-centered. They're provider-centered. And in some cases it's two different sets of providers. It's the prescriber versus the pharmacy, or the prescriber and the pharmacy versus the DEA. And so these systems don't make sense. They're not patient-centered. Again, not making sense is my opinion, not a finding of the study. And all of those things continue in the new REMS. The same sorts of themes, having to do paperwork. Why do we have to submit the ANC? Is there any evidence to show that submitting the ANC or that the ANC is within the normal range or outside of the normal range, is there any evidence to show that that really prevents severe neutropenia? Somebody needs to do a study to show that. If you're going to make everybody who prescribes clozapine enter that data every week or for weekly data every five weeks and go on a website that is sometimes a little bit challenging, if you're going to spend that time, then it's got to have some evidence to show that it works. And those are the changes. And while that may have occurred in the mechanics, it's still a barrier for many people to do that. So I would argue that websites may work a little better. There may be some things that are more intuitive. But all the same challenges that we discovered are still there in one form or another. I think a couple of the things that maybe didn't come out of the study, and this is the Megan opinion as well, and we've seen beyond this is a lot of the unanticipated consequences now. We have our pharmacy benefit managers coming back and auditing pharmacies. If you didn't get a dispense authorization for clozapine, we're not going to pay you for that. Or we're going to fine you. Or we're going to fine you. So now some pharmacies are not doing it because it's just another audit that they're going to have to go through. And with the clozapine REMS currently in that's on hold or whatever status that it's in, pharmacies are still being requested to do these things. We have a Zyprex, a RELPREP provider who's getting audited to look at all their documentation. And so it's, again, not part of the normal process to come back and say now I'm going to have all my records audited. Did I follow all of this appropriately? And this is more workload that's being added. So we're seeing a lot of some unanticipated things on the back end. In the steering committee, there was a big discussion about the effect of REMS on ketamine use. And the steering committee, when we were formulating questions, and we didn't go down this road, but it was clear that their opinion was the fact that, as ketamine, a drug with an approved indication is not used is because it's more convenient to use ketamine, a drug with an unapproved indication, for the same purpose. It's just easier. Megan, every week, sends me articles about pop-up ketamine clinics that open and then, you know, shut down a few weeks later and patients are left holding the bag and they got IV medication that maybe they didn't need or they got ketamine that was sent to their home in a non-controlled fashion. And S-ketamine helped inform the efficacy of this chemical, and yet the REMS pushes us towards its use in a non-approved way because it's too difficult to comply with all of the aspects of the REMS. And S-ketamine is such a smaller amount of ketamine. It is a crazy world we live in. So another unanticipated consequence. And we called this to the attention of the FDA, and, you know, they are aware of that. I don't feel like I can go into all of the discussions that we had with them, but certainly the members of our steering committee, who were folks from national organizations mainly, they had a lot of opinions about that. Go ahead, Jane. I'm just going to hold the microphone. It also seems like, you know, you have all of these cancer medications, you have surgeries where you have these extreme risks, but we, you know, weigh them with the benefits. And it feels like if they're going to look at whether this is preventing agranulocytosis or whether it's preventing, like, dissociation, they also need to compare it to the risk of, like, people committing suicide for these two medications with indications for suicide prevention. And I know that would be hard data to get, but I think when you got that data it would be like, oh, yeah, this is a no-brainer. Deanna Kelly, our colleague at the University of Maryland, cites, and I'm going to – I'm not going to have the numbers precisely correct, but I think that there are 50 more drugs that cause more frequent severe neutropenia than clozapine does, none of which have REMS. Probably including Zyprex or Velprex. Probably. Yeah, probably. So what is the – how is that calculation made? Is this leftover from when clozapine was first approved, when psychiatrists were not practicing more integrated medicine, when they didn't tend to pay as much attention to the patient's medical conditions? When the drug came out, I'm old enough. I was at the first – at the FDA advisory committee on psychopharmacology meeting when clozapine was presented by Sandoz. And that was the concern, and the public was also concerned about the ability of psychiatrists to monitor clozapine. There was no REMS, but there was a different system then. But I think that mentality has continued that a psychiatrist or someone who practices in the behavioral health realm is not going to do as good a job as an oncologist or a rheumatologist or somebody who uses one of these other more toxic agents. So there's a little bit of discrimination in there that I think is unconscious and is leftover from the first approval, and there needs to be a reexamination of that. When we talked about the fact that we need to consider experience with the drug and how things change over time, that's one of the things that's changed over time, is the ability of the prescribers of the drug to monitor for side effects. So I hear you loud and clear. You mentioned the FDA decides whether there's a REMS, but then there's a law that requires the FDA. I wondered if you could explain how those things work together. I'm not a lawyer, and I don't play one on TV. Catherine and Megan, you can chime in if you want to. There's a law requiring that the FDA institute REMS on certain drugs. I have not looked at the law recently, but as I understand it, that is a decision that usually percolates up through the FDA commissioner to the Secretary of Health and Human Services, and they're officially charged with endorsing that decision. The FDA has to decide whether a REMS is strictly an educational REMS or whether it has the Etazu that Catherine talked about. Then they say these are the things that you have to do to the manufacturer, or if there's more than one manufacturer, they require them to have a group. In the case of Clozapine, it's the Clozapine product manufacturers group. They develop the specifics, and then there's some interaction between the FDA and the manufacturer as to how things are implemented. But the assessment of risk is something that's got to take place in the FDA to decide whether to even recommend a drug for REMS. I think the FDA is, on an ongoing basis, considering new data that may suggest that a risk is greater or a risk is lesser, but the FDA uses a very strict method of evaluating scientific evidence that we see in the drug approval process, and it's rare that post-marketing data meets the same strict scientific method as an FDA study for efficacy for approval meets. The FDA has some authority when drugs are approved, but they don't have authority as to how studies are conducted that may show evolution of risk or evolution of risk factors or evolution of health care practice. So that becomes a little bit more complicated process to get them to walk back something once they've decided that there's a need for REMS. And we need to be patient with them, but we need to apply pressure at the same time. Catherine, can you elaborate on that? Yeah, I was just going to add my kind of understanding of the REMS is that when the FDA is kind of reviewing, especially for new drugs, and I think there is a difference when the drug's been out and long versus, you know, and there have been several drugs that have come out with REMS that a couple years later the REMS are gone, right? We haven't seen that with clozapine. But my understanding is when the FDA is looking at the new drug data, it's almost a drug that they would say, you know, we're not going to approve because of this serious side effect. We would not necessarily approve it, but because we have this regulatory mechanism to implement REMS, then it makes them kind of feel more comfortable that they could approve it with the REMS. So that's kind of, you know, it's not a kind of cut and dry, but it's more that that serious side effect doesn't make them think we wouldn't want to approve it, but we have this REMS mechanism to then get a little better handle on that safety mechanism if that kind of helps do that. So I think we're really almost looking at one point in time at the data that's information in that new package, you know, when they're deciding off on that. So clozapine seems to me almost like an outlier, you know, and maybe even Zyprexa relprev has been around for quite a while too. And there are some drugs that have had them longer, but there are several that the REMS go away or lessen, you know, after the years and we get some use on that. And it's not necessarily that your monitoring would go away. You would probably still be monitoring people after their injection or still be getting ANCs when you start somebody on clozapine, but is submitting it, like Ray said, is putting it on a piece of paper and sending it to some, I like to say, unknown black box because, you know, we don't have access to it. We don't know where it's going. Is that helping the risk? It's unfortunate you can't gather all of that information and do some research on it and say let's look at it to see if it actually is doing that component. And I think that was a poignant aspect that actually came out. It's not that the practitioners are saying we don't want to monitor ANC or we don't want to monitor for dissociation. They're like this is part of normal practice, right? That's part of what we would do normally, but now you're making us document and do paperwork and do things outside of what we would already be doing normally. So it's not that they want to not monitor or take care of the patient. It's just that these are processes kind of outside that. So we kind of heard that loud and clear, interestingly. And I do think sometimes with new medicines where maybe you don't know a lot about the medicine, it seems a little bit more sensible, right, because it affects use maybe early on with that. I think the only other one thing I wanted to just ask Megan has started and developed an esketamine clinic. So I think kind of that's why she's, you know. Fingers crossed everything is going to go as planned this summer. Yes, yes. But I think just any kind of experience sharing that, because I think we did hear in kind of the focus group starting, there's a larger inertia needed to start a clinic with a drug that's got a REMS. It is. And we've been back and forth. So our clinic for difficult to treat depression, which started before COVID and then sort of fell apart during COVID and has regained some strength most recently to hopefully open this summer. It has been a lot of discussion. And most recently, even in our last business meeting call on it, was, you know, do we keep going down this esketamine path or are we going to think about ketamine and where are we? And it's really been a focus of, you know, the REMS and thinking about all of that and trying to implement that into our workflow. And, you know, we've done our best of thinking about, you know, all of the double documentation, right? We're going to have to document this all in our chart, plus we're going to have to send it all into REMS and who's going to be responsible for which components and things of that sort. And not that we don't want to do that monitoring, but if we can circumvent some of that workload with the small staff, we're probably going to start with. It's been a – we've had to have a champion, and it's been tough. No, I appreciate that. Yeah, I mean, and, you know, all of the – there's a lot of other things beyond just the REMS, right, the billing, the this, the that, that we're working on too. But I think the REMS is also a big discussion that, you know, who's going to lead and sign that dotted line and say, I'm going to be the person of record to manage all of this and take charge if something goes wrong, that you're on the audit list when someone comes knocking. No, I appreciate that. Yeah, I think with that, if anybody has any other questions. Otherwise, I think thank you for being here, and please reach out to us if anybody has any other thoughts after the session. Thanks, everybody. Thank you.

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