Hello and welcome. I'm Dr. Rob Cotez, Director of the Clinical and Research Program for Psychosis at Grady Health System and Associate Professor at Emory University School of Medicine. I'm so pleased that you are joining us for today's SMI Advisor Webinar, New Clozapine REMS, Staying Informed for the November 15th Changes. Next slide. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. Today's webinar has been designated for 1.0 AMA PRA Category 1 credit for Physicians and 1 Nursing Professional Development Contact Hour. Credit for participating in today's webinar will be available until December 4th, 2021. Slides from the panel today are available in the handouts area found in the lower portion of your control panel. Select the link to download the PDF. Please feel free to submit your questions throughout the presentation by typing them into the question area found at the lower portion of your control panel. We'll reserve about 15 minutes at the end of the presentation today for Q&A. Now I'd like to introduce you to the other faculty for today's webinar, Dr. Donna Rowland and Dr. Megan Ehren. Dr. Donna Rowland is a Clinical Associate Professor and the Director of the Psychiatric Mental Health Nurse Practitioner Program at UT Austin. She is the SMI Nurse Expert for our team. Dr. Megan Ehren is a Professor at the University of Maryland School of Pharmacy and SMI Advisor Pharmacist Consultant. And again, I'm Dr. Rob Cortez. In my clinical work I see patients through a program called P-STAR which focuses on the safe and effective use of clozapine. All right. And here we have the disclosures. Those will be available to you after the presentation as well. All right. As for our learning objectives, after the completion of today's activity, we hope you're able to walk out of here and review the mechanisms, risk factors, and strategies for management of severe neutropenia due to clozapine. We'll also talk about benign ethic neutropenia. You'll be able to assess the function of a REM system and determine how to use REMS for medications commonly prescribed in psychiatry. Most importantly in this session, it'll be about clozapine REMS. And then finally, you'll be able to summarize the changes for prescribers and pharmacists with the updates in clozapine REMS that are going to be effective on November 15th. So for our agenda today, the format will be similar to what we did a few weeks ago, but we'll be interspersing new updates throughout. First, I'll talk a little bit about clozapine and neutropenia. Then Dr. Rowland will talk about changes for new clozapine REMS for prescribers. Dr. Ehret will then talk about changes for pharmacists, and then we'll leave about 20 minutes for question and answer. All right. So first, we're going to talk a little bit about clozapine-induced neutropenia, and then I'm going to mention a couple of remarks about benign ethic neutropenia. Next slide. So neutropenia. Neutropenia is the whole reason why the clozapine REMS system is in place. And Dr. Rowland is going to discuss a little bit more about what is REMS, what are other examples a little bit later in this talk. But I'm going to be talking about a lot of things that are not new and that have been sort of the practice since 2015. So I'm going to go back and highlight a couple of the changes that happened to clozapine REMS in 2015, just right now, because it's going to sort of set the stage, especially for the benign ethic neutropenia part. So first of all, in 2015, there was a new REMS system that replaced the individual clozapine patient registries into a shared program. And I had a fax machine in my house that, in effect of 2015, I no longer had to use, because everything could be then updated electronically without having to fax things directly into the clozapine REMS system. Some pharmacies still abide by the fax though. Okay. And then, rather than using the white blood cell count and absolute neutrophil count, in 2015, we only needed to enter the absolute neutrophil count. And there was really no additional benefit for having separate ANCs and white blood cell count cutoffs. Additionally, the national non-rechallenged master file was discontinued. Also, the thresholds were lower, especially for non-BEN patients. And then, there was a new BEN treatment algorithm that all happened in 2015. Okay. Next slide. So a little bit about clozapine-induced neutropenia. The mechanism is not entirely clear, but we think that most likely it is an immune-mediated reaction rather than direct bone marrow toxicity. As everyone here is aware, you have to get weekly monitoring for the first six months. Then you get every other week monitoring for months six through 12. Then you get once-monthly monitoring indefinitely after someone's been on clozapine for one year. In a meta-analysis, looking at a lot of studies of clozapine-induced neutropenia, the risk of neutropenia was about 3.8% of people exposed to clozapine. The risk of severe neutropenia was 0.9%. Severe neutropenia is an ANC less than 500. But interestingly, the mortality rate when people developed severe neutropenia was low. And importantly, one out of 7,700 people died due to severe neutropenia that were exposed to clozapine. So obviously, one is more than we want out of 7,700, but it's probably not as high as we would have expected. And in part, that's because of the monitoring schedule, especially for the first 12 months that somebody's taking clozapine. So the peak incidence of events of neutropenia was one month after initiation. And then about 90% of cases of severe neutropenia occurred at one year. So one question is, well, what happens if somebody develops severe neutropenia on clozapine and you want to re-challenge them? There's certainly times where the benefit of being on clozapine might outweigh the risks and you want to pursue a re-challenge. So, you know, in clozapine REMS, you can pursue a re-challenge. Often it's done with the existence of neupogen and hematology consultation. In the new clozapine REMS system, you can do this in the patient status form. And we'll talk a little bit more about that later on. But there's basically an option where you can complete a treatment rationale for patients with moderate or severe neutropenia. And on this form, the prescriber now checks a box and attests that the benefits outweigh the risks and you can authorize a re-challenge. And it gives you a date and you can reach, you can, you can sort of authorize it for up to six months. The prescriber, not the designee has to do this. Next slide, please. Benign ending neutropenia. One of the reasons that this is such an important topic is because clozapine remains highly underutilized in the United States in comparison to other countries. And in a recent study of claims data, 4.4% of individuals with schizophrenia spectrum disorder in the United States were prescribed clozapine. And it's commonly cited, you know, that maybe 20 to 30% of people with schizophrenia have TRS, but clozapine is underutilized in the US. I think that that's widely acknowledged. I think one of the big issues though, is that non-Hispanic white individuals are more likely to get clozapine than individuals of other racial or ethnic groups. So, it is, there does appear like there's a lot of evidence of healthcare disparities among clozapine prescribing. And it's quite possible that before 2015, or maybe even now, individuals with BEN are sort of disqualified from prescribers because the ANC looks low and it looks scary. Next slide, please. So, there's going to be a lot more information on these slides that I'm really going to talk about, but you'll be able to have all this information in the handout. So, with benign ending neutropenia, this is some of the wording from the clozapine package insert. And we're going to go over the diagnosis and sort of what the modern diagnosis of BEN looks like. But from the package insert itself, BEN is a condition observed in certain ethnic groups whose average ANC are lower than the standard lab values for neutrophils. Most commonly observed in individuals of African descent, some Middle Eastern ethnic groups, and in other non-Caucasian ethnic groups with darker skin. And then, also importantly, people with BEN are healthy and do not have an increased risk of developing repeated or severe infections. In fact, people who are on clozapine who have BEN may actually have a decreased risk of developing severe neutropenia. All right. And then, the last point here, additional evaluation may be needed to determine if baseline neutropenia is due to BEN. The operative word here is may and not always. So, in some cases, additional evaluation is actually not needed, especially if people have historically had low counts and they're not on other antipsychotics. And you think that the person's background may make sense that they may have BEN. A hematologist actually does not have to be involved in order to make the diagnosis. Next slide. Okay. So, here we have the clozapine REMS BEN algorithm. And the way that various countries around the world have set up clozapine monitoring highly varies, but the U.S. actually has probably the most modern system in the world with very clean criteria and guidance about what actually to do. And again, the United States just uses the ANC, not the white blood cell count. So, for a person with BEN, if a person has an ANC of greater than 1,000, there's no need to do anything and you continue treatment. If somebody has an ANC between 500 and 999, you can continue treatment, but they need three times weekly monitoring. Next slide. Now, once we get to an absolute neutrophil count of less than 500, if you have BEN or if you don't have BEN, that equals severe neutropenia. And clozapine per REMS recommends to interrupt treatment with clozapine. And you need to get daily absolute neutrophil counts until the ANC is greater than 500, and then three times weekly ANCs until the person gets back to a little bit greater than one's baseline. Next slide. A little bit about the history of benign ethnic neutropenia. This has been around, this phenomenon has been around long before the advent of laboratory medicine, but as a field, we really didn't figure this concept out until the 1960s. So, as for the modern definition of BEN, these are individuals who have recurrent ANC of less than 1500 in the absence of other secondary causes of neutropenia, such as infection, HIV is maybe one, drugs, cancer, other autoimmune disorders. So, people with BEN, although the criteria says it's less than 1500, sometimes they can actually have an ANC that's slightly greater, and sometimes people can have an ANC that's lower, like in the 500 to 1000 range. And there's a lot of sort of intra-individual sort of factors that can affect what someone's ANC is, like exercise. And if people exercise just before they get blood work, they can sometimes have a transient increase in ANC. So, there's a lot of things to consider. Next slide. Next slide. Who actually has BEN? So, individuals with African heritage have the strongest association with BEN, but people can have BEN from other nearby Middle Eastern areas, Yemenite Jews or certain Arab populations, for example. And then it's not the race of the person, but it's more the genetics of the person that make the diagnosis. As we mentioned before, BEN is not associated with increased risk of infection or infection-related complications, and people have normally functioning bone marrow morphology. Next slide. All right. So, how do you make the diagnosis of benign ethnic neutropenia? As I said before, you can make a diagnosis of BEN with the clinical criteria without a hematology consult when things are pretty straightforward. And an example of this would be, there's a healthy individual of African heritage who has persistent neutropenia. You see in their EMR, they're on a variety of medications. And then especially when they're not on medications, they still have these low absolute neutrophil count values. But, you know, the real world is sometimes more complicated than that. And, you know, when people come into my clinic and they're referred clozapine, they're sort of referred to us for consideration of clozapine, they're often on a lot of medications, they're often on evalprox, they're on several antipsychotic medications, not just one. So, there's a number of factors, and we'll break those down separately. So, antipsychotics, there's actually a class warning about leukopenia and neutropenia. And neutropenia for non-clozapine antipsychotics is relatively rare, but it does happen. And you can see it. But neutropenia due to divalprox is actually more common. Everybody knows that divalprox causes thrombocytopenia, but it can actually cause neutropenia as well. So, if that individual has a low ANC and they're on divalprox, and they don't need to be on divalprox, maybe there's other options like lithium, then it may be something to consider to stop. And also, interestingly, there does appear to be a dose-dependent response with this. Next slide. So, how do you do testing for benign nethic neutropenia? And you don't always have to do testing if it's a clear case of benign nethic neutropenia. But when there's doubt, and if somebody, you know, if you suspect that maybe the antipsychotic could be lowering someone's ANC a bit, or if there's just not a lot of data that you have about somebody's ANC, there's basically two ways that you can order testing for benign nethic neutropenia. The first is to order red blood cell antigen testing, and then you have them test for the Duffy antigen specifically, because there's actually a lot of antigens on red blood cells. And in my lab, the process is, we order a type and screen, have the person get blood, order a type and screen, we then call the blood bank to order red blood cell antigen testing, and then you specify that you want Duffy antigen testing done. Different labs are going to have different processes. So, when you actually get the report back, you're going to see somebody, maybe FYA, they're going to report FYA, negative or positive, and then FYB, negative or positive. If somebody is FYA negative and FYB negative, that is highly suspicious for BEN. Okay, the other way that you can do it is you can order send-out tests generally for the SNP that's most associated with, that's probably most associated with BEN, but this is a longer process. And as you can see with the study below, you know, interestingly, the sensitivity of doing the Duffy antigen testing and the SNP testing is similar, but, you know, there's slightly higher specificity when you look at the genetic testing. So, really, Duffy antigen testing is a pretty good test if you need to do something, and most of your labs can probably get that for you. Okay, next slide, please. Managing ANC dips. This is something that I think puts a lot of fear into prescribers of clozapine sometimes who haven't managed a lot of this stuff before. So, next slide. Okay, so if you have somebody who has repeated low absolute neutrophil counts, this is for people with BEN or without BEN, the first thing to do is to look at somebody's medication regimen and think, are there medicines that could be contributing to this? You might want to get the divalprox off. You might want to do an HIV test if you don't know somebody's HIV status, but there are other strategies that you can use to sometimes boost the ANC, and sometimes what this does is it prevents somebody from having to come back into the lab three times a week, you know, because often for individuals on clozapine, you're trying to get them to the lab once a week, not to mention three times a week can be very difficult, especially in the beginning. So, there are two options. One option is lithium, and lithium is interesting because lithium causes not just the demargination of neutrophils from the bone marrow into the circulation, but it also directly stimulates the proliferation of neutrophils as well. So, it's making new neutrophils by enhancing production of GCSF. So, you're kind of getting both responses from lithium. All right, and then the next option is filbrastim or neupogen, and this is a little bit more complicated to use because it is a subcutaneous injection, and you have to give it to people sometimes multiple times a week. You can teach people how to administer their own filbrastim, but it is a little bit more tricky to use than, say, something like lithium, but it's quite effective. All right, and typically, in my experience, it can be awfully, it can be challenging, especially like if somebody's on lithium. It can be difficult to wean them off of the lithium because it's possible that the low counts may begin again. So, you kind of have to keep the lithium or neupogen on board most of the time, at least in my experience. All right, so that's what I wanted to say about neutropenia and benign neutropenia, and I will turn things over to Dr. Rowland, who will talk about neuclozapine reps. Thank you, Dr. Potez, for that primer on ANC monitoring, BEN, and for kind of outlining the historical concept of clozapine REMS. Now I'll walk you all through in detail all of the information that is available so far regarding what prescribers must do in order to transition to the new clozapine REMS system. Next. So what is a REMS? So what is a REMS? In 2007, the FDA was granted authority to establish REMS systems, or Risk Evaluation and Mitigation Systems or Strategies, for manufacturers to ensure that drugs' benefits outweighed their risks. And this was done specifically for drugs with potentially dangerous side effects. Essentially, this requires a registry and some level of prescribed monitoring. And examples of drugs of which you're likely familiar are listed here on the slide. And these all use their own specific form of REMS. Next. So what must prescribers do? First of all, prescribers all must recertify with this new REMS system. And the new REMS system will be the only official one beginning November 15th. When you register, you may add designees at that time if you wish, or you can return later to do that. Once you get registered as a clinician, all of your patients must also get enrolled. Finally, there's a new monthly patient status form that's required for each patient to keep them current in the new system. And we'll review all of these steps in detail. There's a URL at the bottom of this slide where you can find the main source document. Next. There's a transitional URL to use at this time, newclozapineREMS.com slash home. On November 15th or shortly thereafter, the usual URL will host the new REMS system. In order to complete prescriber recertification, you must have the following identifiers. NPI number, which will become your login user ID, DEA numbers listed next. And you can see why this might be problematic as a DEA is not required to prescribe clozapine as it's not a DEA controlled substance. So residents, for example, who don't yet have a DEA number cannot currently register with the new REMS system. We are told that REMS will be making this field optional in the near future. At this time, a unique email address is required per site. And this could be problematic for clinicians who work in multiple sites where clozapine is prescribed. The last step in prescriber recertification is taking the knowledge assessment test. This is composed of 12, it should say 12 questions that are essentially the same that were required for the old REMS certification. All of the knowledge assessment content for prescribers is included in the downloadable document called Clozapine and Risk of Neutropenia Guide for Healthcare Providers, which is available now at the new site. And also most of the content in these questions is covered in our webinar slides here today, such as details about BEN, required ANC ranges, clozapine dispensing procedures, et cetera. We may also have time during the Q&A to review some of this content if that's helpful. Next. This slide details a process for adding prescriber designees including office personnel, registered nurses, et cetera. Once the clinician enters their own identifiers, clinicians should send and invite designees through the new REMS system to each designee to finalize the process. Designees can be very helpful, especially during this transitional period. They can enroll patients into your account. They can also submit the monthly patient status form on behalf of the prescriber. Next. Unfortunately, each patient must be enrolled individually. There's no mechanism by which we can submit bulk data. The required patient identifiers are listed here. You'll note that race and ethnicity is required. Also, you must enter a baseline recent ANC result in microliter units with the date. And lastly, you'll know whether they should be flagged with BEN or in hospice care. Next. This is all of the information needed to complete the new monthly patient status form. You'll see the section, prescriber must authorize continuation of therapy if one or more ANC results are missing for the month. It is unclear how tightly this will be followed or whether certain pharmacies will be stricter than others with late ANCs, probably really similar to how things are in practice now. This patient status form essentially replaces the ANC lab reporting form. Next. Again, this PSF is required monthly. There seems to potentially be an option to authorize continued clozapine therapy with missing ANC results. This form is also used for treatment interruptions, for designating a patient with BEN or in hospice care, and for including a treatment rationale when ANC is below the required range, indicating mild, moderate, or severe neutropenia. Next. This is what the top of the PSF form looks like, and this form is available at the site newclozapinerems.com now. Here you can see the patient information required that we have gone over. Next. This is the version of the PSF that would be submitted for a patient requiring monitoring every two weeks, for example. You'll notice that the lab information is entered along with any reasons for missing labs. Note, the prescriber must sign this form in the case of continuing therapy with missing ANC or for treatment interruptions. The treatment rationale and signature is entered at the bottom if the ANC is below the required range. Next. Next. Okay, options for submitting the PSF are detailed here. Clinicians will log in, select Manage Patients, and upload the form. This uploading function is not yet enabled, but will be by November 15th. REMS representatives tell us that there will be the option to input lab information digitally without a file upload for months subsequent to each patient's first submission. Alternatively, PSFs can be faxed in, but please note that ANC lab results submissions do not replace the required PSF. Next. Transition of data. Unfortunately, there is currently no plan to transfer data between the old and new REMS systems. This includes no transfer of designations of Do Not Re-Challenge. We recommend at this time that clinicians or their designees review ANCs in the current system, making note of low ANC results, dates, and treatment interruptions. Again, the new REMS system will be effective on November 15th. We do anticipate that the interim period, especially November, may necessitate some double entry into both systems to assure that Clozapine is dispensed appropriately to our patients. And with all of that, I now will turn it over to Dr. Aratt for an update for pharmacists and pharmacies. Thank you so much. I'm very pleased to be with you guys today to discuss the changes to pharmacies as providers and pharmacists alike are working together to ensure that our patients continue to receive Clozapine. Next slide, please. So for an overview, pharmacies will have to recertify just as prescribers do to continue to dispense Clozapine by November 15th. So it will be important as a final check maybe to confirm with your pharmacies that they have indeed recertified so that they can continue to dispense Clozapine. There is a separate registration for inpatient and outpatient pharmacies. There is a bit of confusion at this point if your pharmacy does both, but they will be able to continue to dispense Clozapine. Additionally, as Dr. Roland said, there is a new document, Clozapine and Risk of Neutropenia. This is a guide for pharmacists as well. And this replaces the guide for healthcare providers. Next slide. What has changed? Pharmacists will now be required to obtain a REMS dispense authorization. And we're calling this an RDA. REMS dispense authorization is a requirement prior to dispensing Clozapine. Previously, this was called a pre-dispense authorization. Upon the first dispensing after enrollment, so after November 15th, when that enrollment has occurred, the RDA will verify that the pharmacy is certified, the patient's been enrolled, and the patient's treatment has not been interrupted or discontinued. This is required that you obtain an RDA. And this, again, will verify all of above, but it will also verify that the patient status form has been completed in the past 37 days. If that patient status form has not been completed in the past 37 days, a pharmacist will not be able to obtain that dispense authorization. Pharmacies can obtain this authorization by either going to the Clozapine REMS website or by emailing the Clozapine REMS contact center. The pharmacies will no longer need to see the ANCs. They will just need to obtain this dispense authorization prior to dispensing. And they will no longer be obtaining these via their previous switch system. That will all be done within the new REMS system now. And again, there is a URL down at the bottom that I will direct you to for additional information on how these URLs may have changed for pharmacies. Next slide, please. The dispense rationale. In the old system, there was no more than three for a patient within a rolling six-month period. Within the new system, the patient is allowed three per year in outpatient pharmacies, and there's no limit in inpatient pharmacies. If there is no patient status form that has been submitted within the past 37 days, a dispense rationale will be provided automatically. And then to provide this rationale, the pharmacist must have an ANC. So they may call to inquire about retrieving that and your NPI number in order to have that dispense rationale authorized to continue to dispense if the patient status form hasn't been sent in. So it will be essential that a system is worked out to make sure that all of the patient status forms are submitted within 37 days so that your patient can continue to receive Clozapine in a timely fashion. Next slide, please. In the old system, pharmacies needed to recertify every two years or they would be deactivated. In the new to the non-rechallenge master file and no prior lab values from the old system will be transferring to the new system. So it's important that if there is anything from the old system that you do rely on that I would suggest that you try to retrieve that within the next two weeks so that you do have that in your hands when that new system goes live because the old system will be closing out on the night of the 14th. Next slide, please. So what hasn't changed? The knowledge assessment questions, there are still those, there should again be 12 total questions. There's been some changes to the language in question seven, but otherwise they are the same verbatim that you would have taken in the previous REMS program as well. And again, we have went over the majority of those questions today in this webinar. Next slide, please. So the new system will not be transferred to the old system. It will be transferred to the new system. Next slide, please. What you might not have known and what we've really been able to get some clarification on in the last couple of weeks is prescribing clozapine for patients who are receiving inpatient care. So many times our patients may be admitted for medical care and if the patient is already enrolled and started on clozapine, when they are admitted to a medical inpatient care, they can continue on clozapine without a certified clozapine provider. If the patient is going to be initiated on clozapine while admitted to an inpatient setting, then a certified prescriber must enroll the patient in the clozapine REMS prior to receiving their first dose of clozapine. So as a patient is admitted medically, if they are already on clozapine, this can be continued by a non-certified REMS provider. And so this is a nice ease that there won't have to be additional REMS certifications across health system. Next slide, please. Another new feature, which is also very nice, is the clozapine REMS has an improved find feature so that you are easily able to locate pharmacies that are participating in the clozapine REMS. This also allows patients to search for pharmacies as well. And so it's a good double check to check for your pharmacies that you frequently use as well to make sure that they are certified and ready to go on November 15th when this goes live as well. Next slide, please. And with that, those are our prepared remarks today. I'm going to go ahead and turn it back over to Dr. Kotez, who will be moderating our question and answers. All right, great. Thank you so much, Dr. Harrod. I was actually wondering, one of the participants from the audience was wondering if we could go back and just review the slide that we lost the audio on briefly. And I'm just wondering if we could go back and just review the slide that we lost the audio on briefly. So I'm wondering, Ben, if you could perhaps take us back a couple of slides in Dr. Harrod's section. I believe that was 41. 41, okay. Thank you, Donna. There are two slides before that. What has changed certification and training? Yes. Perfect. So within the new certification and training program, pharmacies do not have a time stamp on their recertification. Previously, pharmacies had to recertify every two years or they would be deactivated in the system. At this point in the new system, you are certified and there's no time period to recertify. Each pharmacy upon certification will name two authorized representatives. And these representatives then enroll all of the other pharmacists into the REMS program. If either of those representatives would change, then they would need to be updated within the system. The pharmacy staff no longer need to complete the knowledge assessment. Just the authorized representatives complete it and then they invite all of their staff to join the REMS so that they are able to obtain the dispense authorization when they are dispensing clozapine to patients. So it's a little bit different than what might've been done previously where everyone went and enrolled themselves. Now, the authorized representatives will essentially be enrolling their own pharmacy staff. All right, great. Thank you so much for going over that, Dr. Aratt. Could we maybe go to slide 45 real quick before we get to the Q&A? All right, so I just want to take a moment to let everybody know that SMI Advisor is available from your mobile device. Use the SMI Advisor app to access resources, education, and upcoming events, complete rating scales, and even submit questions directly to our team of SMI experts. Download the app at smiadvisor.org slash app. All right, and next slide. All right, so thanks so much to everyone that's been asking questions so far, and we're going to go through a couple of those right now. So this is a question for Dr. Rowland and Aratt. The question is, does data from the ANC lab report populate the status form automatically? So I'm not sure if I understand correctly. Perhaps they're asking if an ANC is faxed in, ANC results are faxed in to REMS. Would that populate automatically? That is no. I'm not sure, Dr. Aratt, if you have anything else to add to that. That was my understanding as well. The form either will need to be filled out online or you can print a copy to fax it in, but there isn't a area to submit ANCs that will self-populate that form. That is something that manually has to be done on a monthly basis, as far as I understand. Yeah, that's also my impression, too. All right, so sort of related to that, another question is, is the PSF going to be made into a PDF so that you can type the information that remains the same so it does not need to be rewritten every time? And I'm happy to field this one. So, you know, right now, the PDF of the PSF, so there is a PDF version of the PSF available. It's just not a fillable PDF. So I know that various, you know, individual organizations have been working on creating a fillable PDF for the PSF. I, for example, have created a fillable PDF that was quite onerous, actually, to make because there's a lot of different boxes. And what I'm going to do is I'm going to check with, you know, maybe check with APA or with CPMG and see if we could make that fillable PDF available because I think that that would save a lot of time. With the fillable PDF, what you can do is, first of all, it's a lot easier to enter the information into the PSF itself. But after that, you can actually save the PDF that has like the initial information on it so you don't have to go back and fill all that information again. But still, the process is a bit laborious. You have to then take the PDF and then upload it into the website each time still at this point, at least for the initial PSF. Okay, next question. Will they fix? Currently, prescriber cannot also be a designee. So, a doctor cannot cover for another doctor by filling out the status form. It has to be done by a designee since the patient on another doctor's caseload won't show up on this individual's patient list. A given email can only be assigned to one role, like a doc as a prescriber. How can we submit patient status form for a colleague who is out? Dr. Kotez, that's a very similar concern that pharmacists are having as well, that you can only have one role within the system. And I know that we have asked for clarification and for a fix on that, but yet we have not heard that, that that has occurred. And so, as far as I'm aware, you can only serve one role in the new REMS. So, they are correct that it's going to be a challenge to cover for someone. And so, the best thing to recommend maybe if you can have an outside designee, but it will be a challenge until that is fixed. This is another question. Is there going to be a place to calculate the ANC on the new website as there is in the current website? It has that calculator. And my understanding is that there is no current calculator in the new website. Dr. Roland or Eric, have you all seen a calculator on the new website? I have not, but I'm looking in there again right now just to be sure. Okay. So, we're double checking on that right now. I have not seen that. I do think that it would be helpful. So, while we're checking on that, I wanted to mention that your professional organizations are at work for you. So, the American Psychiatric, the APA helped actually to organize a listening session with the FDA and CPMG. CPMG is the Clozapine Product Manufacturers Group. And this meeting took place on October 21st. And a lot of what we did was express some concerns that we had about the system. Various organizations were there like APA, the National Council, APHA, APNA, NASHPD, NAMI, and CPMP were represented on the call. Each of the stakeholders had an opportunity to share a little bit about what some of the concerns that they had were. And from the prescriber side, Dr. Rowland and I were able to sort of stress some of the likely increased workflow burdens among other issues, including some of the designee issues. I think that Clozapine, the problem is it's already so underutilized and there's already so many barriers. I think for some people, the idea of filling out a monthly PSF can seem like a bit of a daunting task rather than just to enter the ANC. So I think people are worried that first of all, there's going to be information that during the transition period, there may be issues and that perhaps the perception of additional burden may prevent new people from getting started on Clozapine. So we heard back from them a little bit and they had told us that a number of things, first of all, that the website is not yet completely operational. They gave us some reassurances that the designee issue would be fixed by November 15th. And there's also some talk of hopefully CPMG having a conversation in an ongoing way with stakeholders who are actually prescribing the medicine, dispensing the medicine. So pharmacists, everyone who's part of the team, we hope to be able to have more of a dialogue with CPMG to help move things forward with our input. So I have checked in the system and the monthly patient data entry function is not yet operational. But when you enroll a patient, that function is operational and you must enter the ANC, a baseline or recent ANC, and there is no calculator at that point. But I'm not sure if there will or will not be one in the monthly data upload or field entry section yet. Yeah, so Dr. Roland, that's an important point. With the new patient registration, you have to have an absolute neutrophil count within the last 30 days. Otherwise, it will not let you at least complete the electronic version. You may be able to fax in a version, but the electronic version, sorry, the version on the website prevents you from entering anything past 30 days, which I think there has been some challenges with, especially given the pandemic and some individuals even now in various parts of the country may only be getting blood work three times every three months due to the pandemic, due to particular COVID numbers in that area. So for example, like when I registered all of my patients recently, I was able to register most of them, but some of them hadn't had blood work within the last month due to issues related to the pandemic. So our ability to register them was paused. One of the questions here is, has there been any discussion about delaying the date in which Nuclozapine REMS goes live? I think that a lot of people would like to see that happen, and that was one of the things that was proposed on the call and the listening session. I'm not particularly optimistic that it will be postponed, but it does seem like there are I'm not particularly optimistic that it will be postponed, but it does seem like there could be, they discussed the potential of a transition rationale during the first 90 days after the Nuclozapine REMS system went live. I haven't seen this in writing yet, but it is possible that there'll be a transition rationale for the first 90 days. And I think it's important, Dr. Cortes, as you mentioned that, that I can't stress enough to work with your pharmacies, that many of them are very much overwhelmed right now with COVID and influenza vaccines, and so we want to make sure that they're aware. We've been doing outreach, the Nuclozapine REMS has been doing outreach to make sure that they're registered, but that they are also aware that there may be a transition period, and so that they please call you before they deny any Clozapine dispensing, so that we make sure our patients don't go without. That's an excellent point, Dr. Harrod. Dr. Harrod, I actually, I have a question for you, and I was sort of thinking, what are the challenges in our Clozapine clinic that we face, as we, there's a number of individuals that get Clozapine from our pharmacy that works with a lot of Clozapine. Some individuals get Clozapine from various commercial pharmacies throughout the area. But what's interesting is, even despite the previous system, the Clozapine REMS system, some commercial pharmacies require actual faxed laboratory copies to the pharmacy in order to dispense Clozapine, even outside of Clozapine REMS. I guess I'm wondering, would you think with a new system, it may be possible, perhaps not on November 15th, but eventually, to perhaps avoid that, you know, avoid that obligation, or perhaps there could be some changes in the pharmacy policy? Absolutely. I think with the dispense authorization number, the pharmacy does not need to have a physical copy of the ANC. That is not required under the REMS. They will just be obtaining that authorization number. And so that is their certification that everything has been done. So I'm very hopeful that you will not need to submit anything to a pharmacy. And if a pharmacy is requesting that, that is not part of the REMS. So that doesn't necessarily have to be done. As part of the REMS program, it may be their own internal policies, but it is definitely something that hopefully will be removed moving forward. Because I know that is a struggle, in particular with some pharmacies that may be very old-fashioned. And when we used to collect all of those and keep files on everything, files on everything, now hopefully this new system, since it will have it all there, will require at least that one less back. Thank you so much. It's, yeah, it's easier to fax the labs in 2021 than it was, you know, maybe in 2011. I think there's just better access to technology. It can be done digitally, et cetera. But it is, you know, an additional step. And it does seem like sometimes the policy is inconsistently applied. And it's never really clear when the actual labs need to be faxed or not. So hopefully there may be some silver lining in this. One of the participants had an interesting idea. So this person said that they are a medical director and don't carry their own patients and decided it's better to be enrolled as a designee than as a prescriber, so they can actually cover for other prescribers. So I think that's a nice workaround. One thing I'm curious about, this is a question for Dr. Rowland and Dr. Aaron. I think, what sort of differences in the workflow do you anticipate in new clozapine REMS land? Because I think there may be some differences in the workflow for prescribers and some for pharmacy. And I'm sort of wondering if you all have any ideas about what those changes to the workflow might look like. I can start on that. I know that the nurses that I have as designees in my clinics are, have been in the process of faxing the labs to the pharmacy and to me that they just did that as well. And then the pharmacy on their end was entering the ANCs to generate the ability to dispense the medication. And so I think that's going to be a big switch in retraining all the designees of what they have to put in, not the labs, you know, the lab reports themselves, but these PSF forms are entering it into the online PSF system for subsequent months. So, I think that's going to probably end up being more work on the designees than in the past. I agree. I think from a pharmacy perspective, the authorization numbers are obtained every time that you dispense clozapine. And the other big hurdle will be if the patient does not pick up their clozapine, that those authorization numbers have to be reversed so that the patient can get it at the next place that they're going. So, there's still some concern about how that will work if a patient is admitted and then discharged and some of that. And so we're trying to get clarification on that. But I think that workflow of making sure that that's obtained each time that you dispense the clozapine and keeping track of that will be new for pharmacists. Pharmacists are very used to reviewing all of the ANCs. Like Dr. Roland said, the nurse would fax all of the ANCs to the pharmacy. I think pharmacists are going to be very nervous about not seeing the ANCs because they won't see them on their end. They're just going to be receiving that authorization number that it's fine. And so it may take a little bit of coaching. So, you know, it may take some work with the pharmacist to have them have a comfortability of not seeing the ANCs. Yeah, that's a really important point that I hadn't thought of, Dr. Eric. Thank you for bringing that up. The one question is, if we submit, if the prescribers submit the ANC lab report forms online, would pharmacists be able to access that? We have not been able to get a very solid answer on that particular question. If pharmacists will be able to see all of the ANCs or if they will just be able to generate those authorization to dispense numbers and then get a hard stop if they aren't there. And so we haven't been able to get clear information as to how much the pharmacist is going to be able to see on their end. And, you know, I think another challenge with that is when you're actually filling out, like, let's say PSF, you can check that you're in a normal range. You don't even have to put the ANC value. Correct. Right. That's a difference now. Now you're not even, you don't have to put the value. You're just checking whether it's normal, moderate or severe. Exactly. So one of the members of the audience asked, perhaps if a follow-up webinar in a few weeks might be helpful to compare notes and strategies if needed, I think specifically around some of the workflow issues. One of the things that I'm a little bit concerned about is, you know, for people who are on weekly or every other week frequency, you're submitting a monthly PSF and it's just a little bit more to keep track of now to make sure that you're actually submitting those monthly PSFs. Before, you know, if you got the labs back, you just, you get the labs back and then you put it in REMS and you can just do that very quickly. But now you really have to sort of figure out how, you know, you have to make sure it's done within a one month period. And then you put everything in that occurred in that one month in the PSF. So I think that's going to be a big change in workflow for the prescribers. I do think that the vast majority of prescribers in the United States have clients on monthly monitoring and there's less people on weekly. But for the weekly monitoring folks, it may be a bit more of a challenge. So here's another question from the audience. So the ANC value itself is not required on the PSF? As long as we market at normal range, that is sufficient. Yes, that is correct. And you have to make sure that you choose if someone is in the general patient population or if they're in the BEN population. But if you check normal range, my understanding is the absolute neutral count by itself is not required. So one potential option that we have moving forward to consider is in the virtual forum that's coming up in December, we could consider talking about new clozapine REMS and how it's impacted prescribers and pharmacy and other people in the team. So that might be one option on December 1st that we will discuss. We appreciate that suggestion. And with that, why don't we go ahead and wrap up? We are at the end of the hour. I just wanted to thank everybody. I wanted to thank our two presenters, Dr. Roland and Dr. Aaron for their insights and for their guidance and helping us with this process. And thank you for our great audience with their questions, concerns and strategies for how to move forward. So I think that a lot is going to be coming up about new clozapine REMS. It's a great opportunity to perhaps submit a consult about it. If you're not sure about something, you can go to smiadvisor.com slash submit consult. And you can submit, of course, a consult about clozapine REMS or about any topic related to evidence-based care for SMI. Consultations are free and confidential. Next slide. SMI Advisor is just one of the many SAMHSA initiatives that are designed to help clinicians implement evidence-based care. We encourage you to explore the resources available on the mental health addiction and prevention TTCs, as well as the National Center of Excellence for Eating Disorders and the Suicide Prevention Resource Center. These initiatives cover a broad range of topics from school-based mental health through the opioid epidemic. Next slide. Okay. So to claim credit for participating in today's webinar, you'll need to have met the requisite attendance threshold for your profession. Verification of attendance may take up to five minutes, so be patient. You'll then be able to select next to advance and complete the program evaluation before claiming your credit. So please join us tomorrow on November 12th. Well, I guess November 12th is not tomorrow, but it's coming up next week as Patrick Hendry and Danielle Zuala present, What Does It Take to Establish Mutuality and Form a Successful Peer-to-Peer Specialist Relationship? So this will be available November 12th, 2021, from 3 to 4 p.m. Eastern. Thanks so much for joining us, and until next time, take care. you

Clozapine REMS

Risk Evaluation and Mitigation Strategy

November 15th

prescribers

pharmacists

recertification

patient enrollment

monthly patient status form

dispense authorizations

workflow changes