What can be done to improve clinical trials for patients with chronic wounds? In this new episode of the Scope of Things, host Deborah Borfitz speaks with Dr. Caroline Fife, world-renowned wound care physician and Chief Medical Officer at Intellicure, about the clinical realities of chronic wounds and wound treatment. Dr. Fife shares her thoughts on the “sorry state” of clinical trials for wound care products and what she has learned as the Executive Director of the U.S. Wound Registry that shed some light on the matter. She also discusses how her first clinical trial sparked her drive to improve conditions and the barriers that prevent innovation in the development of new products and technology.
Links from this episode:
Clinical Research News
Scope Summit
Intellicure
What can be done to improve clinical trials for patients with chronic wounds? In this new episode of the Scope of Things, host Deborah Borfitz speaks with Dr. Caroline Fife, world-renowned wound care physician and Chief Medical Officer at Intellicure, about the clinical realities of chronic wounds and wound treatment. Dr. Fife shares her thoughts on the “sorry state” of clinical trials for wound care products and what she has learned as the Executive Director of the U.S. Wound Registry that shed some light on the matter. She also discusses how her first clinical trial sparked her drive to improve conditions and the barriers that prevent innovation in the development of new products and technology.
Links from this episode:
Clinical Research News
Scope Summit
Intellicure
Hello and thanks for joining us for this month's edition of the Scope of Things, a no-nonsense look at the realities and enigmas of clinical research based on those closest to the action who aim for great and, if need be, are willing to shake things up. I'm Deborah Borfitz, senior Science Writer for Clinical Research News. On today's episode we have Dr Caroline Pfeife, a world-renowned wound care physician who serves as Chief Medical Officer at IntelliCure, developer of the first wound care software to integrate with the electronic health care records used by hospitals, who will be speaking about the sorry state of clinical trials for wound care products and sharing what she has learned as Executive Director of the US Wound Registry that shed some light on the matter. Welcome to the show, dr Pfeife.
Speaker 2:Deborah, thanks for having me. I'm excited to do this interview.
Speaker 1:Well, the same here. You have been in the business of treating wounds for over 30 years now and, as you recently shared with me, the needle has moved in a positive direction very little during that time. So let's set the stage for today's discussion by giving listeners a picture of the current clinical reality for patients suffering from a chronic wound. What are you seeing?
Speaker 2:Well, the first thing I want to be clear on is that chronic wounds affect about 16% of Medicare beneficiaries and the fastest growing segment are people under 65 who are Medicare beneficiaries, which means the disabled. And the second thing is, except for a few rare conditions like epidermalysis below sense, some other dermatologic problems, if you have a chronic wound it's because it's a symptom of some other disease you have. So that means I'm a symptomatologist. Chronic wounds are not really a disease and the problem comes in clinical research is when we try to treat them like they are, so we give them imaginary names, like our pets, and then expect for it somehow that to confer a recognizable and reproducible system, and it does not.
Speaker 1:Wow, interesting perspective and not one many people take clearly.
Speaker 2:So here's the irony. I'll just jump in and say here's a problem with clinical trials, deborah, because although my world is wound care, which is a sort of I will acknowledge is a very narrow little world to live in I have a feeling these problems aren't unique to wound care. Clinical trials I bet that in your expertise you can tell me that all clinical, especially focused on the FDA, attempt to exclude as many confounding variables as possible, which means you're looking for the simplest, healthiest, least complicated patient, no matter what kind of trial you're doing, whether it's hypertension or something else. And the irony for us, for chronic wounds let's just take diabetic ulcers, for example is that there are always a symptom of bad diabetes, because the diabetes has to be bad enough to give you peripheral neuropathy. And yet in a clinical trial, what we're looking for is a diabetic patient that has no medical problems.
Speaker 2:I first realized that something was terribly wrong.
Speaker 2:I'm, just as a girl from Texas, small town Texas, and so I sort of chance into starting a wound center, stumble into my first clinical trial in 1997 and had a clinic, a waiting room so packed with patients there was no place to sit down and I had to, which is what we did in 1997, you're too young to remember this we put ads in the paper and went on the radio to enroll in clinical trials.
Speaker 2:I had to put ads in the Houston paper because none of the patients in my clinic were healthy enough for a clinical trial, and in that day and age I didn't know what to call that, except that it was wrong. Now we have a name for it, which is non generalizable clinical trials. The only name that I can use for them is it's wrong for patients, because what happens is we do these clinical trials cost millions in patients that don't reflect the general population, and then the payers will use the exclusion criteria of the clinical trials to decide what they will pay for. So suddenly you now have a product that took millions of dollars to get to market and Only a tiny segment of patients are eligible for it, because the payers want to implement the same ridiculous Narrowness in the choice of patients, with their argument being that we don't know how it will work in the general population. So I Don't have a name for that, except that it's bad business.
Speaker 1:No, yeah, it something struck me that you told me last we spoke, and that was that you had had better luck simply treating patients For their nutritional deficits. Could you just just touch on that really quickly? I just thought that was interesting.
Speaker 2:Yeah, yeah. So here's the I can cut to the chase and I will destroy Millions of investment dollars, maybe billions, oh dear, because the current focus for every manufacturer is the boo boo. Everyone thinks that we're going to come up with some technology focused on the lesion that's going to Revolutionize care and fix all the problems, because the problem surely must be in the boo boo and that's. It's taken me 30 years to realize. It's just not true. And the people that we see who have crime, remember I bet there's no one listening to this who's ever had a chronic wound, wound that hasn't healed?
Speaker 2:It's despite the complexity of this physiologic process it's one of the most complicated, elegant process is the human body, and the most common reason for it to be stopped, quite frankly, is a nutritional deficit. So simply by getting vitamin D fixed. If your vitamin D level is less than D 25 levels, less than 30 you can't make collagen. The simplest, cheapest thing we can do is give people enough vitamin D. Nobody takes enough. Our, our estimated daily requirements are just calculated wrong.
Speaker 2:The other thing is L Arginine, which is the substrate for nitroxide, and everyone now understands what that means in terms of regulating a tissue perfusion, just replacing Basic vitamins and providing L Arginine to most patients with a chronic wound, miracles will happen in a couple of weeks in someone who's had a chronic, non-healing wound, in some cases for months and even years. Now there are things you have to do, which is, if you're walking on a neuropathic foot, then that you have to stop putting pressure on it. So the basic things. I don't want to imply that you don't have to control compression or edema for someone with with a swollen leg, but the idea that somehow we're going to come up with some novel technology to put on the boo boo, excluding the things that are going on systemically with a patient, is, I've been shown to be incorrect For two decades, three decades now, but we keep trying.
Speaker 1:Interesting. Yeah, getting back to wrong wounds and the wrong patients, your mantra that I've been here quite some time now when it comes to clinical trials, this whole mismatch Between you know who's in studies and who those real-world patients are. I mean, do you? Obviously you've already indicated why this matters so much, but do you think people Generally appreciate this, or are they coming to appreciate it? What have you seen change in terms of mindsets?
Speaker 2:Well, I suspect this isn't the only field with dirty secrets. I bet they all have them in every clinical trial. I'm sure that's true for cancer research the stuff we're not supposed to say out loud and my problem is that I don't have a very good filter, so I'm always saying that out loud.
Speaker 2:My kind of gal I don't think there's anybody who knows the field who doesn't know that this is true, and I don't blame the manufacturers, because these are requirements from the FDA. They're doing the trials they were told to do by the agency they have to get Approval or clearance from, so it's not their fault and I would even be okay with it if it didn't have payment implications that could mean that a Unsuspecting physician who wants to do the right thing this new product hits. They're told that it's the greatest things and sliced bread. They use it on everybody they can find and then they get a Medicare audit and pay 100% of the money back, which is what is going on. And by this time the manufacturers moved on. They're quite content because they sold their product and you know their investors are happy and the docs are left Pulling money out of savings and borrowing money to pay back the money that they've lost in a Medicare audit because they used it. So the people who get punished are either patients who don't have access or clinicians who don't realize that they're not going to be able to use it as described. But it's all coming from this concept that the FDA has, which is that wounds are entities that somehow represent a clinical disease process. So this is the other, the quiet part out loud that I can't help but shout, which is you know we do. We have a couple, three syndromes that we give names to and then feel good about that, that we can evaluate them. And Venus leg ulcers are one of the clinical models that are used for Clinical trials, just like diabetic foot ulcers are and sometimes pressure ulcers.
Speaker 2:Well, the problem is and if you ask someone, even a very experienced clinician, ask your favorite internist, what are the most common wounds? He's going to say a diabetic foot ulcer or a venous leg ulcer. That's the knee jerk reaction. That's not true. The most common type of a chronic wound is one that doesn't have a name. It's I hit my leg on the coffee table and it never healed. I can have a whole clinic just from the open dishwasher door. Somebody really needs to redesign dishwashers. But it's the elderly little lady who is on prednisone for rheumatoid arthritis and she has a minor trauma where she banged her leg on her walker and six months have gone by and it's not better.
Speaker 2:So that's the most common wound in the United States, at least in the over 65 group, and no research is done on them because we can't give them a name. So I say that it's like pets, we give things these imaginary names and then we feel like we know them and that's just silly, so we exclude. And, by the way, actually I like the most common wound is not the chronic ulcer. If I hit my leg, it's a surgical dehiscence. That's the most. Did you know that's the most common wound in the United States is a surgical dehiscence, as the wound that got sewed up and then split open and everyone thinks those are due to infection. They're not. Those are primarily due to nutritional deficits and they get secondarily infected after they open up. The second most common wound is I hit my leg on the coffee table. Guess how much research is directed at those two top problems? None.
Speaker 1:None, wow, wow. Okay, if the buck stops with the FDA, how can the agency have gotten this so wrong for so long? What is enabling these misperceptions to persist, I guess?
Speaker 2:It's the idea that diabetic foot ulcers and venous ulcers are the things that are common. First of all, they've been sold this bill of goods that that's the most common wound type. It's simply not, and we can prove that with claims analysis for Medicare and other payers. So part of it is a successful and incorrect marketing campaign for diabetic foot ulcers and venous ulcers, because there is a lot of technology directed at that. So you get this vicious cycle. If you believe that that's the most common thing, and because it has a name, so the FDA believes it to be an entity, then they will agree to sponsor trials, believing that somehow wounds collected under that rubric enough resemble each other that they could constitute a clinical trial population.
Speaker 2:And so our big problem in, for example, surgical dehiscence is how do you fight a battle on all fronts when a huge reason for surgical dehiscence are, for example, the medications that a patient takes, which inhibit wound healing? There's exactly zero conversation about the long list of medications that actually inhibit wound healing. Although billions are invested in clinical trials, no one wants to talk about the side effects of certain drugs to prevent wounds from healing. That has to be done To prevent wounds from healing. That has no traction at all. So part of it any answer to your question is the FDA wants a clinically identifiable syndrome and they believe that diabetic foot ulcers and venous ulcers represent one and the big bucket of patients with problems don't have have so many multifactorial contributions that nobody wants to tackle that as a bucket.
Speaker 1:Interesting. Have you ever tried approaching the agency with these concerns? I did.
Speaker 2:The FDA actually had a fantastic. I can send you a link if that's useful. They did really. I have to give them credit. Thanks in large part to Dev Verma, a very fascinating just to put a tail into COVID. So it had to be virtual two-day meeting on wound healing with a cast of everybody who's anybody and they let me give a talk on the wounds with no name.
Speaker 2:And my concern over why this doesn't represent the population. So at least they've heard it and I'd be happy to share with you my slide deck from that meeting because it's all online and I can provide the links if anyone's interested in that. It was well by the FDA. They still have not quite figured out what to do about it, but at least they have heard the story.
Speaker 1:Definitely do that and I will provide a link to it. We'll write a story about this podcast and we'll include those links in that story. So please do that for sure. Yeah, I mean any other attempts to kind, of course, correct that you're aware of and where have they gone? You know right or wrong. I mean little baby steps in the right direction.
Speaker 2:Yeah, there's some hope, there's some baby steps, and one of the baby steps has been to try to get to more generalizable trials by including more comorbid disease in diabetic foot ulcer and venous ulcer trials, and I'm very grateful. And oh, I didn't even talk about the worst thing about DFU and VLU. Here's the worst thing about the DFU trials and that is that they've almost entirely, until very recently, focused on the most superficial foot ulcers that a patient can have that involve no deep structures and therefore are not limb threatening. And again, that's because these companies need to have a product that appears to induce healing and they certainly don't want one that appears to fail. But here's the fascinating way in which researchers have been done up to now, at least in diabetic foot ulcers, and that is, you don't want to pay for a trial that costs more, than that lasts more than 12 or 16 weeks, so you work backwards to figure out what's the largest size of a wound that could conceivably close in that time frame and then you make the trial just short enough that all of those wounds wouldn't close. Naturally Sounds so crafty, it's very crafty. So that way, the product you're testing you're not actually testing whether or not it heals a wound that wouldn't heal. You're testing whether it heals a wound faster that was going to heal anyway. But you can truthfully claim that X percent of the patients with your product healed, compared to X percent of those without your product, have a V value. That's impressive. And everyone pat on the back and says see, your product heals wounds. If they had run the trial for 26 weeks or 36 weeks, the controls would have also most likely healed. So that's the sort of terrible craftiness of the way things have been designed. There are finally some manufacturers with the guts to say our product is so good that we're willing to tackle these more severe diabetic foot ulcers and, by the way, the reason it matters.
Speaker 2:We did a very interesting registry.
Speaker 2:We did a very interesting study once where we took a consortium of six clinics that were all using the same documentation system and contributing data to the registry, which is how we knew and they were doing, between these six clinics, five prospective randomized controlled trials for new products and we compared the inclusion and exclusion criteria for their two diabetic foot ulcers and three venous trials, or maybe it was the other way three DFU and two venous, but we compared the inclusion exclusion criteria for the wounds that were being enrolled in these trials, with actual patients being seen by these six clinics, and we showed that there was almost no overlap in the ones being enrolled from the ones they were actually caring for, for the real venous ulcers were five times larger and the patients had multiple ones of them.
Speaker 2:The real diabetic foot ulcers were far more severe and they had patients had many comorbid diseases. So the Venn diagram of who we treat and who we enroll in trials doesn't even overlap. They're separate circles on a continuum. So that's the reason that having more generalizable trials matters not only for enrolling patients that have some comorbid diseases, but also to heal on their own. And that is finally starting to happen. And we're using registry data to help design those trials because, since they've never been done, the manufacturers with the courage to do this don't actually know how big or how deep these wounds are that can be enrolled, because nobody's ever done that trial, so it's uncharted territory for them.
Speaker 1:It's use of real world data into a clinical trial environment, and that's what you're assisting with. Correct? Yeah, yeah.
Speaker 2:That's been my mission. In the 90s I did the first few prospective trials for products that came out in wound care. We were very excited in the 90s. We thought this is it. I'd already been running a wound center for nine years and thinking, ok, finally we're going to fix this with technology and if you look at the healing rates of diabetic foot ulcers and venous ulcers between 1990 and now, they're not really much changed. I will admit that the patients are much sicker, but it doesn't look at a superficial glance like all of this technology and the billions of dollars we're spending have made much difference. Although that's not completely true, it's still somewhat true that technology hasn't solved the problem, and a lot of it has to do with the misdirection of technology and the fact our clinical trials don't represent what we really need.
Speaker 1:Yeah, yeah. Ok. So we've been doing clinical trials, but it's been more than 20 years now since you have done one, as I understand it, and for all the reasons we've been talking about. Are you alone in your despair? Is there an army of would be investigators out there who share your concerns and likewise retreated? Can we make people care more?
Speaker 2:Talk about that, well that's actually why I said as early as 2000, I don't know what you call this, except that it's wrong and I was serving on the Institutional Review Board for the University of Texas Health Science Center in Houston and I knew these trials weren't unethical, they were just wrong. So I said there has to be some way to figure out. What will it take for us to collect data in such a systematized, reproducible way that the FDA would be willing to trust the data collected clinically, either for expansion of indications or for new types of wounds? We haven't gotten there yet. It's still a battle. But I will say that's what I'm still committed to, unless somebody shows up with a truly generalizable trial and they're getting closer. So I'm a little bit more willing to back away from my firm decision that somebody has to find a better way to do this, and so maybe I'll give you a definite maybe that it might be true. But what I'd wish is how we could enable the use of real world data for enhancing or expanding FDA policy.
Speaker 1:So the day that you start doing clinical trials again may not be too far off. And when you say you're waiting, are you waiting for any particular response from a particular, like a research group, from the FDA, collaborators, manufacturers? What are you waiting for? Who are you waiting on?
Speaker 2:Manufacturers are finally getting the courage to say we think our product is so good we tackle the ones that really aren't going to heal on their own, and so that's exciting. When a manufacturer comes to us and says look, we want to do a clinical trial and we're interested in rolling people with the following diseases. We're not going to a priori exclude everyone with heart failure, everyone with a hemoglobin A1C that's over 10, everyone who's got the following problems, I start to perk up because then you're talking about my people and they're willing to enroll ulcers that are into the joint capsule, for example. Like, finally, we're starting to talk about things that matter. Personally, I still think that the answer is going to be systemic and not local. So I am waiting for the day that somebody says here's this thing that's going to finally correct some of the systemic problems we have.
Speaker 2:And of course, the sad reality is that some of the systemic things are so inexpensive and not novel that many of the barriers could be overcome if we did really basic thing, that no investor is going to want to spend millions of dollars investing in because you could get it off Amazon, and that therein is the problem that we have for these patients, which is that nutritional assessments. In many cases, you know, it's almost impossible to get a vitamin D level on a patient unless you say that they have a falling problem, Like you can't just get a vitamin D level covered because they have a chronic wound. But our sort of ridiculous bias against the idea of evaluating nutritional status is really horrific. And none of the supplements or the products that may be valuable and I'm just talking about vitamins and L-Arginine are covered by payers. So we have a blindness to one of the most basic problems that costs the US billions of dollars, especially with surgical behistoses being the most common problem and perhaps preventable with a nutritional evaluation prior to surgery. But we won't do that. So that sort of gets to this whole issue of the barrier to real innovation is that no one will fund a study that doesn't clearly notch into the reimbursement structure that we currently have.
Speaker 2:So a truly novel product. It's totally understandable that people want to know what their risk is if they're going to fund new technology, and so the new technology we see just keeps being different iterations of the technology we've already got, because a true innovation that was disruptive to the current reimbursement structure couldn't get funded. Nobody would risk it. So let's say it turns out to be a nutritional supplement, no one would fund that study because they're not covered by payers. There's no logical financial win for a truly novel technology. I think that's probably the biggest problem. That was one of the questions the FDA had, which is why don't we see true innovation? And the answer is there is no true innovation unless it fits into the reimbursement structure that we currently have, and that's a circular logic that's not good for patients.
Speaker 1:Yeah, wow, and this may or may not get what I want to ask you about last year and that is kind of a plug, I guess possibly for your Wound Care Evidence Summit, where I know payers have been involved in the past. I've seen you've hosted these from time to time in Bethesda, Maryland, where supposedly all the outstanding issues with Wound Care clinical trials were being openly discussed and there was researchers there and regulators and clinicians and manufacturers and policymakers et cetera. What has come out of those dialogues and are we getting anywhere? Is there hope?
Speaker 2:We don't. It's hard for me to point to a clear win. You first have to identify the problems, but here's one of the things that I think is a barrier, and that is at least as far as Medicare is concerned. We're not allowed to talk about cost, but the private payers and Medicare always consider cost. And here's my suspicion, when you try to link together the developers of products with the entities that pay for them, is that the payers know whether a new technology has really made a difference.
Speaker 2:There was a long time that I was reluctant to consider healthcare cost as a surrogate for benefit, but I'm on board with that now.
Speaker 2:If a technology really bends the cost curve, if it really works, it will bend the cost curve. So what I suspect, and what frustrates me, is that we don't have access to the cost information that the private payers and even the Medicare use in order to make these decisions. If we can talk openly about cost and we could ask the question does this technology really make care cheaper, which would imply that it actually makes something better, then I think we'd be able to tell the truth and shame the devil, and I think right now the payers know when a new technology does nothing but ramp up cost and doesn't really fix problems. There must be some way that we could all have access to the cost data that they're looking at, and then we could look honestly at whether technology is making a difference. I feel like that's the thing that would change the most, and it would also enable us to have better conversations with payers over what they're going to pay for Cost effectiveness research?
Speaker 2:Yes, I think it's time for us to start talking more about cost, and that that's a fair surrogate for whether something really works.
Speaker 1:I love that. Thank you so much. Well, you have been, as always, crystal clear as to why the current state of wound care and wound care research kind of makes you mad, and it's a righteous anger. Dr Fife, it's good to know there's someone out there who cares so much and so passionately about what really matters the patients on the receiving end of all this. Please don't stop shouting from the rooftops, because what you do matters, and please, please, keep me posted on any degree of progress as the days, months, years, progress here, and thanks so much for taking the time to be on the show today.
Speaker 2:Deborah, thank you for caring about these patients.
Speaker 1:I absolutely do as you do. I'm vicariously through you, kara. You make your case so well and, as always, everyone out there big thank you to you for listening in. If you're not yet subscribed to this podcast, please consider going to Apple Podcasts and doing so right now, so you don't miss your monthly dose of news and perspectives. You'll be hard-pressed to find anywhere else and, if you're up for it, I'd be so very grateful if you'd leave a rating and review on Apple Podcasts too. One final note, if you like today's conversation. It is only a glimpse of what you can expect from the presenters and panelists we have on tap for CHI's Summit for Clinical Ops Executives Europe, aka Scope Europe. Please plan to join us October 17th and 18th in Barcelona, spain, and please be sure to use the discount code SOT10 for a 10% discount off any current rate. For more information, visit scopesummeteuropecom. Bye for now.