Chapters Transcript Apligraf RCT and Real World Evidence – Dr. Robert Kirsner Investigating the Reliability and Transferability of Randomized Controlled Trials Based on Real-World Evidence Hello and welcome to today's Wounds webinar. Today's presentation is entitled Investigating the reliability and transferability of randomized controlled trials based on Real World evidence. My name is Julie Gould, Senior Manager of editorial Operations for Wounds Research. And we're happy to have you joining us today. We'd like to thank organogenesis for sponsoring today's presentation during the webinar. Feel free to submit questions and comments for our speakers by using the question submission section on your screen. At the end of the presentation. We'll try to answer as many of your questions as we can in the time allowed today. We are very pleased to welcome our featured speaker, Robert S Kirsner, MD PhD FAA D. Doctor Kirchner is chairman and Harvey Blank professor in the Doctor Philip Frost, Department of Dermatology and cutaneous Surgery at the University of Miami Miller School of Medicine. He is Chief of Dermatology at the University of Miami Hospital and Clinics and Jackson Memorial Hospital and also directs the University of Miami Hospital Wound Center. We are very happy to have him join us today with that. I will turn it over to our presenter and thank you again for joining us. Hi everyone. I'm Robert Kirzner and I'm thrilled to be discussing on this, uh webinar investigating the reliability and transferability of randomized control trials based on real world experience. Now, I've had a significant interest in diabetic foot ulcers and venous leg ulcers and other chronic wounds for a long time. Uh, here is one of our papers from the New England Journal of Medicine in 2017. Uh And here is uh another paper uh uh about 13 years early, also from the New England Journal of Medicine, looking at the care of diabetic foot ulcers. I've also had a significant interest in outcomes, both clinical and often economic outcomes of tissue engineered skin such as Agra, which at the time was called a graph skin. Here's our experience from uh nearly 20 years ago. Um And this is a more recent publication looking at uh uh evidence and cost effectiveness and advanced cellular tissue products for treatment and diabetic foot ulcers. So I'm really excited to be presenting this webinar and kind of giving a whole spectrum of evidence and outcomes uh for uh uh for APL gra and uh in, in the setting of tissue engineered skin. Now, when we often talk about evidence, we think about this evidence pyramid uh that's been utilized where at the, the very lowest level uh is expert opinion. And then as you go up the pyramid, uh you go up to case re series and reports and case control studies cohort studies and then you get to randomize uh control trials. Um And then at the very top are an analysis or a or a collection of those randomized control trials in either system systematic reviews or me analysis. Um And this evidence that is being presented is one usually considered one type of evidence um where oftentimes especially at the highest level of randomized control trials, uh predefined data is collected during a limited period of time. And in those systematic reviews that data is analyzed um uh in, in concert. Um but what's missing from this data pyramid, this evidence pyramid is a real world um experience also called RWE. And in the real world experience really reflects how products are used in the real world that effects they have in clinical practice as opposed to what's was done in the very highly controlled setting of a clinical trial. And I wanna kind of kind of talk about this difference between um efficacy, which is clinical trial data. And that what that tells us is that in the perfect world of a clinical trial in this experiment that was carried out can a product work? And this is different than the concept of effectiveness where it, you don't answer the question? Can it work in the idealized setting? But does it work in your typical clinical practice? And um so there's efficacy and effectiveness and really the rest of the talk is gonna be kind of juggling and talking about these two different types of evidence, clinical trials, data efficacy can work and clinical practice, data effectiveness. And does it work? Now, just to remind you that uh what uh what we're talking about randomized control trials, uh Use control patients who receive no treatment or conventional treatment or in some cases of placebo patients are randomly assigned to one test group or another. Um And uh there's an avoidance of investigative bias by masking procedures, either single, double or in some cases, triple masking procedures. When the statisticians are also masked. And there's a development of a sound ethical basis for the conduct of research. And for most people, this is often thought of the the highest level of of clinical investigation. But there's this other piece that I began to allude to this idea of real world experience where this is the clinical evidence regarding the usage and potential benefits or risks of a medical product devi derived from the analysis of Real World practice data. And it can be generated by various different study designs including but not limited to randomized trials, including large sample trials, pragmatic trials or also observational studies, whether they be prospective and retrospective. And we'll dive deeper into this uh methodology of Real world evidence in a in a little bit. So just to put this idea of these kind of two sides of a coin in comparison between randomized control trials, RCTS and Real World evidence. Rwes. Uh the purpose is I stated, one is efficacy data. The other its effectiveness. One is an experimental se setting. A really uh the highest level of clinical experimentation. The other is a real world setting. Um The the trial, the randomized control trial is designed where in real world practice, this is what actually happened in practice. And as a result of that, a lot of things are different as opposed to the strict eligibility, strict treatments in a fixed pattern, a homogeneous study group, there's a flexibility and eligibility who would in the practice would receive a product. There's a variable pattern of treatment, not on a regular or fixed pattern of treatment. And the study group may be a heterogeneous group of patients and the patient follow up and monitoring. As opposed to a design interval, the follow up may be variable or changeable. Furthermore, when you look at what you can compare to in a randomized control trial, you have a presigned comparative group within real world evidence, you have the ability to compare one set of data from that real world data set to a different uh group. So there's many different ways to analyze real world data. So what are the advantages and limitations of each one of this? These different types of data? Well, the advantages of randomized control trials is that this randomization has the ability of washing out biases because you're randomly assigning patient to one group or another. And it's also easier to blind or mask than observational studies. Uh And the results can be analyzed with well known statistical tools and the populations of participate, uh participating individuals are clearly defined through inclusion and exclusion criteria. Getting a very homogeneous population, which can be analyzed quite easily. On the other hand, there are limitations because it's very expensive in terms of both time and money to carry out these studies, you only are able to study someone who wants to participate in an experiment so that the group that's being studied may not be representative of a real world population. And of course, there's loss to follow up, which may be attributed to the treatment. On the other hand, real world evidence also has advantages and limitations. There's less time and cost when compared to a randomized controlled trial. And this is some research that can't be done with uh with an RCT methodology. Certainly it's very safe research and high risk patients because they're getting the treatment in a clinical practice. Uh And these patients would normally be excluded from any analysis in a randomized controlled trial. There's rapid access and easier information and data retrieval. Um And you can create certain models or select certain populations to analyze. Uh With this, on the other hand, there are also also limitations. You'd need a fairly large and robust sample size that needs to be collected because you have to control for a lot of the heterogeneity that is in this population, you need time for data quality management, you need statistical expertise. And because patients didn't necessarily sign up for this. Meaning when they got the treatment in a practice, they didn't know that their data was gonna be analyzed. There's always a risk of lack of private confidentiality and of course lost data. Um Importantly, when these studies are carried out, you need standardized research protocols before you carry out the research. Otherwise you introduce the risk of bias. Um And uh and also the possibility that the the the interpretation of the data may be incorrect. So these are some of the limitations. Now, I'm gonna focus the remainder of the presentation really talking about the reliability and also the transferability of randomized control trial uh data based on real world experience. And I'm gonna focus on the bi layered living cellular construct, uh also known as Agra. So we're gonna look at both parts of the, the coin that efficacy data and the effectiveness data in combination to get a real sense of how this product works for your patients. And just to remind you what ali is. Um it's, it's made from uh living cells, uh foreskin, fibroblasts and keratinocytes. And the way it's created is that uh human foreskin fiber blasts are placed into a collagen matrix. Uh Once it's placed in that collagen matrix, it begins to secrete other extracellular matrix proteins as well as growth factors in cytokines. After several days, six days uh keratinocytes also from foreskin are added. Um It grows out into a monolayer over the period of four more days and a day 10 is raised up to an air liquid interface and allow allowed to stratify. Um so that you have a uh living dermal component and the living epidermal component that's uh fully functional and stratified. And if you look at the cartoon, it looks very similar uh in histology uh to normal healthy skin uh with uh living cells in the, in the dermis and epidermis and a fully stratified and functional epidermis. Um And in addition to those cells and matrix, it also secretes growth factors and cytokines uh to help uh as one of the mechanisms to help heal wounds. Now, at the University of Miami where I'm the chair, uh we carried out a study to look at how AFL works that we know there's growth factors in cytokines secreted by the products. But what are those growth factors in cytokines do? So, what we did was we carried out a study looking at nonhealing venous leg ulcers that hadn't gotten smaller after four weeks of standard of care, which is uh which is debris in and uh and uh and compression and patients were randomized to either receiving Agra or con continuing standard of care or conventional therapy. Uh Biopsies were taken at both the wound edge and wound base at baseline. Agra was applied and then biopsies were taken a week later and then a host of end points were looked at through gene expression and micro array analysis. Um uh micro RN A analysis and protein analysis and to make a very complicated and long story short for the purpose of this webinar. What we found was that when you take a, a nonhealing wound that has unresponsive and dysfunctional keratinocytes and fibro blasts, a disorganized extracellular matrix and unbalanced matrix, metallic proteases, dysfunctioning growth factor signaling and significant fibrosis and apply a graph. It actually transforms that wound into what looks like not a chronic wound but an acute wound with activated keratinocytes at the wound edge, restored fibroblast function in the womb bed, normalizing of the extracellular matrix production and M MP balance. There's also a correction and regulation of growth factor signaling and a down regulation of the fibrosis seen in the chronic wound. So, by applying this skin, you actually transform the chronic wound to look much more like a wound that's ready to heal an acute wound. No, let me begin to talk about um the data that I've been that I highlighted or I will highlight. Um And again, I'm gonna look at both randomized control trial data and real world evidence. And together you'll get a more complete picture of how agra helps to heal both venous leg ulcers and diabetic foot ulcers to a greater extent and also uh faster. So, first and foremost, I want to highlight the randomized controlled trial evidence for each of these wounds. And these are robust data sets, high quality data that has gone to the FDA. The Food and drug administration, not for clearance, but for approval, which is a higher level of analysis and scrutiny so that the the the best trials were carried out for regulatory approval. In addition, there's a number of different real world observational studies with hundreds of patients and venous leg ulcers and diabetic foot ulcers. Um And just to remind you of all the products that are out there. Uh Only Agra has conducted randomized control trials for FDA approval for both the venous leg ulcers and diabetic foot ulcers. So let's let's start with the diabetic foot ulcer and I don't have to tell you too much about how important healing a diabetic foot ulcers. And is because this is not only a, a serious complication for the patient, it has serious complications, it's a complication of diabetes and neuropathy and in some case, vascular disease. Uh but those patients are at high risk for developing osteomyelitis amputation and even death. And we know just reminding you of some numbers that 85% of leg amputations are preceded by a diabetic fif uh foot ulcer. 15% of diabetic foot ulcers result in a lower extremity amputation which unfortunately occurs every five minutes in the United States. And patients with diabetic foot ulcers or diabetes related amputations um have greater mortality if you look at their five year mortality rates. It's much more common, uh, than, uh, uh, and much higher than you'd suspect. Certainly higher, 50% higher than diabetes alone and similar, if not higher, uh, than many common cancers higher than, for example, breast and prostate cancer. Now, when we see a patient with a diabetic foot ulcer, one of the things or several of the things we think about is what is the likelihood of healing. And we know that several factors play an important role in the healing of diabetic foot ulcers. One is ulcer size and the ulcer, the other is ulcer duration. So, if you think of um, small diabetic foot ulcers, those diabetic foot ulcers less than um, two centimeters squared, they don't heal in the majority of cases, 39% of the time they heal, but they heal better than those diabetic foot ulcers that are even larger, for example, greater than four centimeters squared, which that only one in five patients heal in a reasonable amount of time. 20 weeks. On the other hand, if you look at how long an ulcer has been there, the chronicity of the wound, again, ulcers that are present less than six months still don't heal great. Only 41% of the patients heal at 20 weeks. But again, that's substantially better than wounds that are present greater than 12 months, that only heal a quarter of the time. So, while diabetic foot ulcers, whether regardless of their size and duration are difficult to heal. Having larger wounds of longer duration puts them at higher risk for non healing. Now, I want to share with you uh the randomized control trial uh of AGRA that led to FDA approval. This was carried out in the, in the uh in the late 20th century and uh was finally, was published in 2001 and led to FDA approval. Uh that same year, this was a study of uh 208 patients randomized either Agra or control group. Uh The mean age, the percentage that were male, the BM I the wound area and the wound duration were all um uh similar between the two groups. Importantly, and as you can see, these were not trivial wounds in terms of size or duration, three centimeters on average and 11 months in duration on average. So these were difficult to heal wounds. Um But if you look at the data in this randomized control trial, uh 56% of patients treated with Agra plus conventional therapy. In this case, offloading and debridement healed in 12 weeks compared to 38% of patients with conventional therapy alone. And that's a a statistically significant and clinically meaningful. Importantly, not only do those wounds heal, uh to a greater extent, they heal faster wound treated with Agra that healed, healed in two months compared to three months, a month, nearly a month faster with uh patients who received agra and we're talking about wounds that are high risk for complications, getting a wound healed faster is of utmost importance and that combination of healing patients to a greater extent and healing patients faster also reduced the complications seen with diabetic foot ulcers. A lower incidence of osteomyelitis 2.7% compared to 10.4%. Again, statistically significant and importantly, a lower incidence of amputation in the study limb Uh after six months, 6.3% compared to uh 15.6%. So you saw greater healing, faster healing and reduced complications in this highly controlled randomized controlled trial that led to FDA approval. Now, what about the real world experience? Now, often time in real world experience, we have the ability to not compare patients to just uh untreated control but to other products on the market. And here's a study that looked at uh the healing of diabetic foot ulcers compared to a placental products fix, looking at several different time frames at week 12 and a week 24. And you could see if you look at the frequency of diabetic foot ulcer closure on your left that nearly 50% 48% of patients treat with agra healed with uh um uh with uh healed it by uh 12 weeks compared to 28% of patients who were treated with Epic Fix. And if you go out to uh uh 24 weeks, you see 72% of patients through with a graph healed compared to 47%. Um And if you look at the meantime of closure, you see that it's again dramatically faster, uh 13 weeks compared to 26 weeks. So you see in this very nicely, several important things. The first thing is you see the same types of healing rates observed in this the efficacy trial, the randomized control trial observed here in a randomized uh uh uh in real world evidence. And you also see the um uh the ability to heal wounds faster. Uh And, and that is very important when we talk about the ability to reduce the complications of these very uh uh uh detrimental uh wounds, diabetic foot ulcers, um diabetic foot ulcers treated with Agra has faster healing. And as I mentioned, this reduces the burden on patients and on the health care system. So, by reducing or healing patients faster with Agra, um you, the data in the real world suggests that it releases amputations and the ability to uh to reduce the health care costs. And in a me, an analysis of Medicare claims for diabetic foot ulcers comparing about 500 Agra treated patients compared to 500 uh similar convention care treating counterparts during an 18 month fo follow up, Agra patients had a 80 28% reduction in lower limb amputations, 32% fewer emergency department visits and uh 33% fewer days hospitalized and the average reduction in health care was over $5000. So here we have data taking, the randomized control trade is showing that in real world, the benefits are extended for our patients who we see in our clinics on a daily basis. Now, um this publication by the American Diabetes Association, which I was one of the co authors kind of nicely highlights uh some of the data I've begun to talk about. This is a table taken from that publication looking at various different um uh uh types of treatment. Uh There's growth factors such as recombinant platelet derived growth factor or Regranex platelet release. Eight. There is uh human uh cellular constructs such as a GRA here called HS A or human skin equivalent. And then the dermal construct uh derm gra, there are a cellular constructs uh integra and uh oasis uh uh uh in the first two. And then, uh and then there are also uh placental membranes and then other treatments such as negative pressure and hyperbaric oxygen therapy. The first thing I wanted to point out is under each uh is the number of patients uh treated in randomized control trials. And that's very important uh because you'll see in a second that uh uh uh statistical power is improved when and you get a G A likelihood of greater truth when more patients are enrolled. And you could see the second level is the randomized control trial data. I already highlighted the data for uh Agra for uh this is for diabetic foot ulcers, which I showed you already. And the time to closure, which I highlighted only four of the products are FDA approved. And interesting when a uh analysis was done of the study quality, it's those forced um products that had FDA approval, that their study had highest quality and of those uh products on this table, uh only four of them had additional randomized control trials and only four of them have efficacy data. And you are highlighting a graph. You can see ali the HSE has the high quality randomized control trial data, additional support of randomized control trial for diabetic foot ulcers and also effectiveness data or real world data that have already started the show and now highlighting the importance of sample size. This is an example of some studies that were done on small sample sizes and larger sample sizes of two convent uh products that are used for R for diabetic foot ulcers, the total contact cast and the instant total contact cast. And what I want to show you is that when you have small sample sizes, sometimes you have exaggerated healing rates. But as you go from 20 patients in a trial to 80 patients in each uh in a trial, you can see that the you get to the more likely get to the ground truth of what really happens with those treatments going from night, midnight or high uh eighties and uh to 75 and 45 respectively for total contact cast and instant total contact cast. So the sample size for randomized control trials is very important when you think about the Generali for this to the real world population. Now, just to, I want to show you some early work that we did. I've done, I published a number of studies, some that already were highlighted. But because this was the first study we did, I want to just kind of explain to you a little bit about this methodology of looking at real world data. And what in this uh data set that we used. This is data from 90 wound clinics and hospitals in 30 states, looking at patients with diabetic foot ulcers. These were wound centers at the time, it was part of the curative uh health system. And we looked at the data over a four year period and looked at several different uh advanced therapies. We started with 100 and 20,000 patients with wounds of which 70,000 had diabetes. So this was a very large Generali Zable data set and it was validated. Uh looking at uh uh the data and what we did in this publication, uh we started with uh 2500 patients with 9500 wounds who had received at least one advanced therapy. We uh we were able to look at the data, make sure we would eliminate those patients with missing, missing identify identifiers and still had a robust data set of patients who received advanced therapies. Of those. About uh uh nearly 1900 patients had received platelet derive growth factor. About 446 patients receive the bilayer cell therapy or Agra and 100 and 25 patients received a platelet release date and then analyzing the data. What we we were able to compare to uh the differences in patient age gender, uh comorbidity such as hypertension trauma and osteomyelitis. And in general, uh we saw that the bi layered living cellular construct, patients were slightly older. Uh uh the uh the platelet derived growth factor of the Klein or a granite group. Uh patients had a slightly more likely to have high blood pressure. We also looked at wound specific characteristics and found that the platelet derived growth factor patients generally was slightly smaller in wound area. Uh and the platelet release patients were slightly deeper in wound depth. Um but patients were treated later with the Agra compared to the Regranex or the platelet release aid. So we're able to analyze the data but also control for these differences in a statistical uh model, you the cox proportional model. And this is the survival curve. And what the survival means is the survival of the wound. So the the the lower the curve, the less survival of the wound and the better the patients did compared the yellow line, which is a graph of the blue line which is Regranex and the green line, which is the platelet release A. And what we found was that uh the Agra or bilayer living cellular therapy group was 40% more likely to heal than wounds treated with platelet release A and 31% more likely to heal than patients treated with um platelet derived growth factor. Uh controlling for those differences in baseline characteristics I shared with you. So this is the type of analysis we do with real world data. Interesting what we also found that all of the groups did better if they were treated earlier. And I think this reinforces the idea that we give standard of care for a specific amount of time and then move on to advanced therapy. If the patient isn't healing typically after four weeks and if we can get uh patients moved on to advanced therapy in four weeks, the patient outcomes are improved. Now, we've done other studies. Uh Here's another study looking at uh uh the dehydrated amniotic membrane or uh Epyx uh and uh using similar methodologies, what we found looking at complete healing. There was a dramatic improvement in complete healing with Agra both a week 12 and 24 and faster healing. And I had highlighted this data earlier, but I wanted to reinforce it uh comparing it to the, the epifix data because of uh uh highlighting the similar methodology that we used. Um And here is using this cox regression analysis uh model where we're able to control for any differences in baseline characteristics. And also, again, showing faster healing and better healing with the Agra group compared to the um the epifix group. Now, I highlighted the, the data for diabetic foot ulcers. Um I wanna move on and talk about the data for uh for venous leg ulcers, looking at both real world data and randomized control trial data. Now, I wanna um uh remind you that similar uh to um a diabetic foot ulcers, wound size and wound duration is also very important with patients who have venous leg ulcers. Uh People have dichotomies, uh wounds into wounds that are bigger and larger than 10 centimeters or present shorter or greater than 12 months. And you could see that uh uh for smaller wounds uh um are more likely to heal and there's a greater chance of non healing with larger wounds and uh uh whether or not they're of short duration or of long duration. So, let's dive deep into the uh Agra data for randomized control trial. Again, this was a study that led to FDA approval. Uh And this was uh uh was the first uh uh product that uh received FDA approval for treatment of chronic wound venous leg ulcers. Again, looking at the baseline characteristics, age gender, uh wound area and wound duration. Uh They were very similar with Agra treat wounds being slightly larger 13.3 centimeters again, these are large wounds and uh and uh a greater percentage uh being uh a uh greater than 12 months or one year duration. This was carried out. This large randomized control trial is carried out at uh 15 clinical sites throughout the United States. Looking at on your left, the incidence of complete wound closure after 24 weeks. Uh 57% of patients on this very difficult and refractory group healed with uh uh Agra plus conventional therapy or uh compression therapy and debridement compared to 40%. And this was statistically and clinically significant. Similar to what we saw with diabetic foot ulcers, we saw a dramatic reduction in the time of wound closure. So those patients that healed with agri he did so 85 days faster than patients with uh who have received conventional therapy. And this also re re was statistically significant. Again, you're getting both greater complete healing and faster healing with Agra treated wounds. So that's the data that led to FDA approval, the experiment, the randomized control trial. But what about the real world experience? What about what happens in diabetic foot ulcers? And I want to share with you the data from three venous leg ulcer studies. Now where Agra was compared to oasis Fokin and primatrix, I've already showed you the diabetic foot ulcer uh study looking at EP fix. And here you see three different um uh comparisons looking at uh apple versus oasis on your left versus the skin in the middle and versus prime matrix in the right, all of which had very large sample sizes. Uh 1400 Agra treatment wounds on your left. 600 fif uh excuse me, uh 688 A graft treated wounds in the center and 893 A graft treated wounds on your right. Compared to uh over between 103 and 400 treated wounds with oasis, theo skin and Primatrix. And what you found both for 12 weeks and 24 weeks. In all cases, there was faster healing uh and uh and greater healing in patients treated with ali gra. Uh If you, we if we just focus on the 24 weeks for sake of uh uh uh of uh of time, 50% compared to 41% with oasis, 65% compared to 41% with tho skin and 55% compared to 43% uh compared to prime matrix. And if you recall back to those agra treated wounds in the randomized control trial data, this healing is very similar. This healing rate in real life, 50 60% is very similar to what we saw in the randomized controlled trial. Additionally, we saw 4452 and 30% 37% faster healing for those agra treated wounds compared to oasis, the skin and primatrix uh in um respectively. Now, what about the effect of uh um agra in with regard to health care system, we showed that it heals faster and it heals better. Uh And we know that venous leg ulcers have a dramatic uh burden on the health care system. 78% more hospital days. If you have a venous leg ulcer, 50% more emergency visits and 60% more days of home health. And the direct cost of caring for a venous leg ulcer is estimated to be uh uh about $15 billion in each year. If you compare a group of patients with a venous leg ulcer compared to those who are similar, but without a venous leg ulcer. Now looking at data uh of patients who received agram. Uh it's uh it's compared to patients who received conventional therapy alone such as the naboo. Uh there were uh three more months over a course of a period of time and of a year in a healed state. So a dramatic improvement in quality of life and a dramatic reduction in annual costs. So $7500 less annual cost for caring for those patients if you can heal those patients faster and more uh effectively. So I've showed you a lot of data and what I wanted to now uh summarize the data and conclude. So while there are really two sides of evidence, there is the experiment, the randomized control trials and there's real world data, which is really what happens in the, in the clinics. And while real world uh while randomized controlled trials don't replicate real world experience. We do. I did show you in highlight that the larger and more rigorous randomized controlled trials can better predict what might occur in real world practice. And I showed you that Agra which was studied in large populations uh in in randomized controlled trials with high quality data, those results stood up better than smaller and less rigorous randomized controlled trials when, when these products were used in clinical practice. And importantly, it's in to look at both sides of the data. Coin randomized control trials. And real world data should help drive your clinical decision making because it's important if a product can work, but it's also very important if a to make sure a product does work in your hands in the clinic. So in my final conclusion of this webinar is Agra has the best clinical trial and clinical practice data for stalled venous leg ulcers and diabetic foot ulcers. We know how Agra works. It transforms wounds from a chronic to acute state and restores the normal uh healing functions. It's backed by this without any comparison, unmatched quality, clinical evidence to heal uh venous leg ulcers and die diabetic foot ulcers. And in addition to that, it's the only product that went through the rigorous uh FDA approval process for diabetic foot ulcers and for venous leg ulcers in a positive way that has and also has supported data in real world experience. So, with that, I wanna thank you very much for your attention and I look forward to any questions that I may be able to answer. Thank you very much. Well, thank you to our presenter, Doctor Kirsner for a great webinar. Uh We now like to open up the discussion to our audience. Um Just as a reminder if you have any questions for our speaker, you can send them in using the question box on your screen. We're gonna try and get to as many questions as we can in our remaining time. So, Doctor Kirsner, our first question for you today is how often is Agra applied? Well, thank you very much uh um for that question. And um it turns out that uh in the randomized control trials um that led to its FDA approval. Uh There were uh typically Agra was applied on a weekly basis um in the venous leg ulcer trial. Actually, it was uh five applications over a three week period. So it was even more frequently. But in the diabetic foot ulcer trial, it was weekly and in clinical practice, uh that's typical the frequency where you get the optimal results. Um So I would say that while some uh clinical variation occurs and patients who see you in practice don't always um uh come back on a weekly basis. But if they, if, if you were going to try to optimize the effect of Agra, I would say weekly would be the way to go. Excellent. Uh Next question, there is evidence to support several skin substitutes for the treatment of chronic wounds over conventional wound care methods. Will you speak to how Agra compares? Well, it's, it's, it's an excellent question because there's lots of skin substitutes and of that very large number of skin substitutes, only a small minority have evidence and of the ones that have evidence, only a smaller minority have high quality evidence. Now it turns out that Ali has the best evidence of any of any product. And when I say that I'm basing that on a number of different factors. The first is that there's a high quality randomized control trials and not one but several indications. It's FDA approved for both diabetic foot ulcers and venous leg ulcers. And that means that there were high quality randomized controlled trials. Secondly, there have been confirmatory trials in some of those indications. So other randomized controlled trials that confirmed the results that were seen and approved by the FDA. In addition to the randomized control trials, there's also Real world and real life experience. Uh both uh looking at uh Apple uh in real world experience plus app compared to other products in in real world experience. And what's really quite interesting is that uh the results that were seen in real world experience, meaning the number of patients healed and the time it takes to heal them was very similar to what was seen in the randomized control trials. And it really does speak to the quality of the trials that you can replicate those results in real world practice. Um And then of course, uh having been around for 23 years for venous leg ulcers and 21 years for diabetic foot ulcers that is approved. Uh there is a wealth of uh of experience in many people's hands. Uh moving its uh its utility. So for all those reasons, Apple really has a uh the best data to drive clinical practice. Great is applic graft FDA approved for pressure injuries. Uh No, it's not currently FDA approved there. It's approved for the two indications, diabetic foot ulcers and venous leg ulcers. And of course, if it, if one uses it for uh pressure ulcers, uh that's uh uh what we call an off level indication. All right. Is there any evidence to support cost effectiveness for agra treatment in non healing wounds? Yes. So I've been interested in, you know, the health economics and uh and uh uh the cost effectiveness of a lot of products including appli for for many years. In fact, uh I recall uh when Apple first came out and we were beginning to get our clinical experiencing experience publishing our paper comparing our historic data to uh own personal experience with using it. And over the years, many other people have done similar work and um and certainly uh in, in with diabetic foot ulcers in the randomized controlled trials, it was shown that not only did a speed the healing of uh of diabetic diabetic foot ulcers, which of course, the the shorter amount of time you have the pro uh have a wound. Uh the less expensive it is to care for it. But it also reduced very, very costly and important complications such as uh bone infections, osteomyelitis was reduced when patients received Agra compared to standard of care and amputations, very expensive complication uh in economic cost, not all besides the cost, the psychological and other costs of having an amputation. Uh But by reducing the number of amputations, you dramatically reduce the um uh the cost of care. A more recent data for venous leg ulcers, for example, suggests that looking at two match populations of patients, if you uh patient received Agra, it reduced the cost of care by by over $13,000 during that episode of care for the Venus for refractory venous leg ulcers. There is a substantial amount of data suggesting that in the right patients, those patients who are not improving the standard of care after four weeks of care, early use of Agra will in the reduce the overall cost of care in a substantial way. In addition to getting better health outcomes, faster healing and reduce complications. Um in your experience, does Agra actually quote take like an autograph? No, it doesn't. And and certainly we have, uh, oh, you know, certainly 20 somewhat, 22 years, 23 years of clinical experience and, and those involved in the clinical trial, uh, before it was approved, uh, have a lot of experience with that beyond those 23 years. And, and, um, and, uh, certainly, uh, it looks like skin so, you know, histologically and clinically it feels like a, uh, uh, a piece of split or partial thickness skin. Uh, but it doesn't act that way, meaning it doesn't behave that way when you, uh, when you put it on, uh, and, uh, on a wound, um, even if it looks like it's still there, if you go back and sample, uh, the area that you think Agra is there and look for, uh, remnants of the app, it's there in the minority of cases. Uh, and this has been done in venous leg ulcers and acute wounds, um, showing that the skin is replaced by the host own skin, uh, very early on. Um, so it doesn't work by graft take. It's, uh, it, it, it's silently replaced by the hosts own skin, but we do know, or at least we know, uh, uh, in, in, in some way how Apple does work, especially in chronic wounds. And this was some work done by Rif Gaston Marton, which and others at, at a University of Miami where they took patients with refractory, um, uh, uh venous leg ulcers and sample the wound and then applied Agra and then resample, not the Agra, but the wound itself. And, and they found that as early as one week after a single application of Agra, the wound changes. Um what actually happens is this chronic wound begins to look and behave like an acute wound. Um the in the or the cytokines and and growth factors change the type of inflammation changes from a chronic wound that's in a nonhealing phenotype to an acute wound. That's in a healing phenotype. You get up regulation of the patient's own cells to produce more growth, uh stimulatory cytokines, and you also change the degree of scarring fibrosis in the wound bed to behave less like a chronic wound and look more like an acute wound. Um So we think that not only is the delivery of cytokines and growth factors from the Agra itself to the wound. But these other actions, the transformation from chronic inflammation to acute inflammation, the upregulation of cells to produce healing cytokines and the reduction of the pro fibrotic state that is uh that's seen in chronic wounds are all part of the very important mechanism that APL possesses to help heal wounds. Excellent. Uh Next from our audience. Uh what is Agra made out of? So it's a, so it's a, it's a bi layered living skin equivalent. Uh The the dermis is made of neonatal foreskin, fibroblasts and it's placed in a, in a bovine type one collagen matrix when you put the cells in that matrix, those cells begin to secrete their own neomi. So, uh collagen and other matrix uh matrix proteins are produced um over top of that, uh that dermis is placed uh neonatal keratinocytes. Actually, they're from actually a different donor. So you have one cells from one donor and the other cells from a different donor. The keratinocytes are placed over this over this. Uh uh they grow into a, on a layer in about uh in, in four days. So the dermis grows for six days. The the keratinocytes spread and cover the whole uh dermis in about four more days. And then at day 10, it's lifted out of an aqueous environment up into what's called an air liquid interface. Some of the uh um uh growth materials that are placed in the uh in the in uh that are changed, calcium has changed calcium and growth factors changed a little bit. And then at this, with this air liquid interface, the epiderm is stratified. So it looks like uh after three weeks total, looks like a stratified um epithelium very similar to human skin. Of course, it's primarily made of keratinocytes. It doesn't have melanocytes or, or, or the l your hand cells or professional immune cells. So, you have a, a dermis made of neonatal fibroblasts in a, in a matrix overlaid by stratified keratinocytes also derived from neonatal cells. Uh Is there data to support the use of APL and chronic VL us greater than one year duration. So, um uh in the clinical trials that led to FDA approval, uh one of the interesting observations that was made was that not only does Agra work, but its greatest impact are on the most difficult, hard to heal wounds. And this has been studied in a number of different ways. But in that pivotal trial that led to FDA approval, uh the way it was studied, uh was that they looked at or they stratified wounds that were present longer or less than one year. And they use that, that one year cut off as determining someone having a really hard to heal wound. And the delta, the change between what Ali Graf did and what standard of care did was even greater in those hard to heal wounds. So while Ali works in all wounds that are, are present more than four weeks, uh, you shouldn't be shied away from the most difficult wounds because they're really, really hard to heal and Agra can still reverse tho uh those wounds and make them make them heal. So, yeah, there's actually quite good evidence that in wounds greater than one year, those very hard to heal wounds that a graph works quite well. All righty. Well, thank you, Doctor Kerner for answering all of those questions. We're just about out of time. Um, so we can start to close down for the day. Uh First, I'd like to thank organogenesis for sponsoring today's uh presentation. Doctor Kerner. Do you have any closing comments? No, I, I think that uh um we've been very, very lucky over the past uh two to have uh a great product uh like APL of bail for us to uh to treat our difficult to heal patients. Um And not only do we, each of us see who use it c clinically. Uh Those results are backed up by a high quality evidence, both randomized control trial and real world evidence that truly support the use of this product for refractory VLDFU. So good luck out there everyone using this product. And I hope you have a great rest of your day. Published October 22, 2024 Created by
