Transcript
SAWC Difference Makers Podcast
Episode 8: Predicting Healing: The Epidemiology Behind Everyday Wound Care
Host: Robert Kirsner, MD, PhD
Guest: David Margolis, MD, PhD
Intro:
Welcome to the SAWC Difference Makers Podcast. We share stories that inspire, mentorship that equips, and the evidence behind innovations improving wound care.
Robert Kirsner, MD, PhD:
I’m Robert Kirsner, and this is the SAWC Difference Makers Podcast.
Welcome to SAWC Difference Makers. Today’s guest is the legendary David Margolis, professor of dermatology and epidemiology at the University of Pennsylvania. Thank you so much for being here, David.
David Margolis, MD, PhD:
Thank you for having me.
Dr. Kirsner:
It’s great to have you on the podcast. We’ve known each other for many years, and your contributions to wound healing and to dermatology have been immense. I want to dive into some of those things you’ve done and are doing over the next 20 minutes or so.
David, I’d like you to tell the audience how you got to wound healing. What was your backstory, your path to the field?
Dr. Margolis:
It’s a story that probably won’t be repeated, to be honest. I originally trained in internal medicine and then trained in dermatology. During my last year of dermatology residency, I was asked to help run a wound clinic. This was in, I guess, the early 90s.
At the time, there were lots of consortiums and the beginning of consensus conferences, and they needed a token dermatologist because the people from Miami had already been there for too long. They asked me to join.
At the time I joined, I literally was just out of residency. I would sit on the panels, often with much more senior people, who would talk a lot about how they treated patients and how patients should be treated. It actually made me feel uncomfortable because I wasn’t quite sure what it was based on, other than their own opinions.
At the time, I got involved in getting degrees in epidemiology. I got a master’s degree and then a PhD, and then came back to the notion of whether there was some way we could better understand chronic wounds by using large data sets, patients’ records, and things along those lines, which was somewhat novel in the early 90s, as you probably remember.
Dr. Kirsner:
I do. I do very well.
In some circles, there is—or maybe you can either agree or disagree—a bias against data that’s derived from epidemiology. I’m not entirely sure why, because many of the things the lay public knows, like smoking is bad, weren’t derived from randomized controlled trials, but really more population-based work.
Have you encountered that? And what are your thoughts about whether a bias exists and why?
Dr. Margolis:
I do think early on there was a bias against anything that wasn’t out of the basic science level—the concept of doing wet-bench research.
Why that was, I don’t fully understand. When you do wet-bench research, there are often small sample sizes. You may be using one or two mice. You may be using some cell line that really only represents one individual. There are sometimes preconceived notions about what the response and answer should be, and sometimes experiments are tailored along those ways.
There certainly early on in my career was a bias that I wasn’t doing real research, if that’s part of what you mean.
The reality is that humans are different than mice and certainly different than most cell cultures, as I’m sure you’ve seen in your own work. There is an importance to understanding the human phenomenon and the heterogeneity of being human. The need for that is often large data sets.
Sometimes the data sets aren’t of high quality, and that needs to be well understood. There are certainly a few large data sets being used right now quite popularly, especially in dermatology journals, that are poor quality. But if you do careful research, just like any research that you do, it’s careful. Hopefully, meaningful things will come out of it.
Dr. Kirsner:
Among the things that the wound healers listening to this may or may not know is that what they do on a daily basis is often directly related to your work.
Could you tell us a little bit about how that work looking at data began to predict whether a patient is going to heal, and how you took pretty complex data and eventually made it simple enough that a clinician in practice can use it and begin to make clinical decisions based on your work?
Dr. Margolis:
I was wondering what work you were talking about, but now I better understand.
You’re right. Some of the early work on trying to predict who with a chronic wound might heal in 16 weeks or 20 weeks, or whatever time frame, was work that I was involved in. It came out of using what at that point would be viewed as large data sets. Those large data sets were from a wound healing company that was smart enough to realize they needed to collect routine data sets.
This was before electronic medical records, but they were collecting routine data sets from patients who were seen in multiple different sites across the country. Part of the reason they were doing that, I believe, is that they wanted to understand just what was being seen. They didn’t necessarily know what to do with that data.
We were fortunate enough to get funding to look at their data and begin to look at whether you could find data that occurred when somebody enrolled in, in this case, a new wound care center, and see whether you could in some ways predict whether they might heal.
Again, at the time, that was considered novel. It was a large data set of about 20,000 to 40,000 individuals. Nowadays, large data sets are literally millions of individuals. At that time, there were some limitations on computation, believe it or not, and those were viewed as big data sets.
There were concerns along the way about whether the data itself was reliable or valid, but a lot of the data was fairly simple, and they trained their wound care providers pretty well.
The observations we made, which I believe is what you’re talking about, were really based on things like how big the wound was when somebody came to the wound care center, how old the wound was, and then a lot of other variables that you might obtain when somebody first comes to your office.
In fact, those variables—wound size and wound duration—proved to be fairly important for venous leg ulcers in terms of predicting who was going to do well. I think our original studies were 20 weeks because that’s what the FDA was using for clinical trials.
In terms of diabetic foot ulcers, there needed to be some marker added to that that talked about anatomic depth. Those models were right about 66% to 70% of the time.
Somebody could easily say, “Well, what does wound size really mean?” or “What does wound duration really mean?” To be honest, I know what wound size means because somebody measures it.
What does wound duration mean? It’s what the patient decided in terms of the age of their wound before they came in, but it may mean other things. It may be a cytokine pattern. It may be an infection pattern or all sorts of other things. If somebody just looks at their wound and says, “Oh, it must be six months old,” or something along those lines.
But the truth of the matter is, even though others and I have tried to redefine those risk factors, nothing has really come to the front that redefines them.
At the same time, we also looked at whether you could look at a shorter duration than 20 weeks. At four weeks and how things change in four weeks in terms of wound size, you can often predict what’s going to happen 16 to 20 weeks later. Those are the original contributions from using large data, which I believe you’re alluding to. Those things were done a number of years ago, but as you point out, they still have stood the test of time.
Dr. Kirsner:
The NIH has a whole effort for diabetic foot ulcers looking for biomarkers that might be better than what you came up with. To date, after a number of years, they haven’t come up with anything that’s better yet.
So you’re a classic. And in fact, David, you’re not just a classic. I’ll tell the audience, when we were at a dermatology meeting, a young mentee came up and declared that David was an icon.
Dr. Margolis:
Look what happened to him. He left wound care and went into atopic dermatitis, so he was confused to begin with.
Dr. Kirsner:
Do you feel that the future of epidemiology, whether it’s in wound healing or dermatology, is in good shape? Do you think it has a robust future? Have you done your iconic work to create the next generation? And how does that contribution fit into your plethora of other things you’ve done?
Dr. Margolis:
Let me just back up for one second.
We’ve also done studies trying to create better prognostic models and get rid of just wound size and wound age. Certainly, you’re right, in the diabetic foot consortium, there are lots of people looking for biomarkers. I’m sure at some point somebody will come up with better things.
Those two things shouldn’t stand the test of time. In some ways, in my mind, there’s a problem that they still exist and that people are still using them. They’re very simple to use clinically, and they may live for years because of that, but somebody will at some point understand what size of the wound has to do with whether somebody’s going to heal, and what the duration of the wound has to do with whether somebody heals. There have got to be other things, and there have got to be explanations for it.
Dr. Kirsner:
You’re like Babe Ruth. You know, 714 stood for a long time and eventually was overtaken.
Dr. Margolis:
Yeah, but people were juicing then.
In terms of the future, I do think you are right. When we started—and you’re an epidemiologist too—when we started as epidemiologists in dermatology, it was somewhat unique. There were maybe a handful of people worldwide who were both dermatologists and had some degree in health sciences or epidemiology, or whatever you want to call that.
Now there are dozens of people who are on academic faculties throughout the world who are doing good work using epidemiologic or health services principles, whatever you want to call it. I’m sure I’m not being as inclusive as I should be. And that is really good.
There is a huge benefit that any clinical field will have by having people do studies to better understand the natural history of disease. Whether those studies are merely descriptive, which is often a complaint of translational scientists—although everybody’s work is descriptive to some point—or whether they’re more analytic and more explanatory or causal in nature really depends on the study, the design, and what you can do with the data you’re working with.
Hopefully I answered your question. I forgot what it was already. I’m getting old. I apologize.
Dr. Kirsner:
You’re getting madder, not older.
People, because of your contributions, may think, “Oh, Dave Margolis, he’s an epidemiologist,” or “He’s a dermatoepidemiologist, a wound-healing epidemiologist.” But you pointed out that having knowledge about the field is critically important. You’ve done work, especially in stem cells and growth factors, that is quite interesting, including with hyperbaric oxygen.
Could you tell the audience a little bit about that work? Because many people may not view that as something that would be in your purview.
Dr. Margolis:
Certainly as an epidemiologist, I’ve incorporated other factors in my studies. I’ve been able to do that because of the willingness of colleagues to collaborate.
You are right. We’ve done studies looking at growth factors and circulating growth factors. We’ve done studies looking at genetics and genomics. We’ve done studies using larger data sets to look at behavioral things. All of those were because others were willing to collaborate.
For people who have, let’s say, powerful or interesting translational or bench approaches, you can often take those to some degree and look at huge numbers of people, and then discover what’s going to go on.
You are right. We did one of the first gene transfer studies that was funded by the dermatology institute. It was actually one of the first ones that was done because of the timing. We were able to do that because we had done work looking at prognostic factors. We could create inclusion and exclusion criteria of individuals who we knew weren’t going to heal well.
I was working at an institution at that point where gene transfer was novel, and they were one of the few places in the world that was really doing it. At that point, the gene transfer was with an adenoviral vector. There was funding available, and there was plenty of knowledge of what PDGF potentially could do to heal a chronic wound.
We were able to do a phase 1 study—it was probably 20-some years ago—doing gene transfer using an adenoviral vector in people who had chronic venous leg ulcers. We actually also had funding to look at diabetic foot ulcers, but ultimately, because of other issues, it never happened. That was part of the novelty of being in an academic center that had lots of resources and lots of interesting people, and better understanding who might heal and who might not heal.
Dr. Kirsner:
It is interesting because I started off by saying that your work is being used by people in clinics every day to predict healing. At the same time, you mentioned that the work also impacts clinical research.
Do you envision that clinical research is going to change and our traditional randomized controlled trials will evolve into something different, especially in light of the fact that there haven’t been that many wound healing products that have been approved? Do you foresee that somehow the power of statistical analysis or trial design will drive another generation of ways we look at evidence?
Dr. Margolis:
That’s a fascinating question and statement.
I can still remember being on an American Academy of Dermatology session that was run by one of your mentors, Dr. Eaglstein. At the time, I was asked to speak about the future of clinical trials in chronic wounds. I think they predated ClinicalTrials.gov. The FDA published all the clinical trials that were being done, so I basically just reviewed what was published because that’s what was known. These weren’t published papers. It was a government website.
Around the same time, there was a review published by a group in the UK where they had looked at all the cytokines that had become available and what their outcomes were. I’m sure you remember at the time, everybody was excited. All these cytokines caused growth in chronic wounds, and everything was going to be better in a year or a month.
I basically got up and talked about it and talked about the failures of these approaches, which is part of science. Dr. Eaglstein corrected me, saying how bright the future was and how, in just a year or two, there would be all these great products.
But you’re right. In hindsight, we’re 20 years later, and there has been lots of investigation and a lot of good science, but a lot of it hasn’t really translated to humans.
The question is why. Is it because, as I think you’re implying, the clinical trial structure that the FDA uses—phase 1, 2, 3, and maybe 4—doesn’t really fit the chronic wound paradigm? Or is there something else?
I don’t know the answer to that. So much of medicine, the advances in medicine that we know in our lifetime, has been because of rigorous clinical trials, with the assumption that the heterogeneity humans bring to clinical trials can somehow be randomized, and you can somehow find products that get past that variance in disease definition and disease severity.
Those models worked for so many things. But there is this concern that a venous leg ulcer is not a venous leg ulcer, that a diabetic foot ulcer is not a diabetic foot ulcer, and that maybe what caused it is the same, but what is keeping it chronic may vary tremendously. In that case, that kind of system might not work so well.
I don’t know the answer to that, to be fair. I trained as a pharmacoepidemiologist, as you mentioned, and pharmacoepidemiologists worry a lot about what happens once a drug becomes available. The first thousand people who experience a drug are the ones in the FDA trials. It’s the next 10,000 or 100,000 people where you find out if something really works in the community at large and if it’s safe.
To get rid of that makes me worry about safety. There certainly have been some discussions with the current administration about getting rid of it.
But you’re right. On the other end, if there’s not enough homogeneity in what a chronic wound is, you may never find anything that really works. So I don’t know. That’s beyond my pay grade. That’s why I’m just here as a faculty member. I’m not involved in the safety of the country.
Dr. Kirsner:
You touched upon some clinical trials and a little bit about the clinical trial structure, especially the FDA. You also touched upon real-world data, data sets from companies, and other data sets.
Do you ever see the field moving to trials or using real-world populations more than preconceived populations to answer questions?
Dr. Margolis:
I would love to see that happen because I do think that’s important. The problem is, how would it happen?
If the FDA created a system where there was, let’s say, provisional approval, you could do some sort of studies that show things are safe and show that they’re doing what you expect them to do, and that in the strictest clinical trial setting, the efficacy looks like it’s there.
The effectiveness is what you’re going to find out in the real-world setting, which is what you’re talking about: how well something really works in the community at large. That is so important, as you have seen, I’m sure, in your career, not just treating chronic wounds, but everything.
There are things where there is a huge amount of hype, the clinical trial data looks great, and then three years later you can’t remember the name of the product because it just didn’t work.
To include more of that data, I think, is great. Could you accelerate it so you’re not doing as many phase 3 studies before you allow things to go forward? Yeah, I think that would be a good idea. But you would have to create some system where it was still just provisional, and people didn’t get involved in the money being generated from the product and want to continue something because they’re generating money, even though it may not be safe or may not work.
Dr. Kirsner:
David, as we come toward the end, we’ve talked about you straddling these two worlds: a clinical world of patients with diseases, whether wound healing or skin diseases, and the other world of data science that you’ve led and trained people to continue to lead.
I was going to ask you if you had one life preserver, would you throw it to the dermatologist or to the epidemiologist? Who would you save?
But I’m going to ask you an even tougher question. You’ve been very productive, not only at work, but at home. You have a whole brood of children, and your daughter is going to get married. Would you rather have her marry an epidemiologist or a dermatologist?
Dr. Margolis:
That’s a good question. I’d rather she marry the person who makes her happy. It shouldn’t be my decision. It should be hers.
Dr. Kirsner:
Well, there you have it. Equanimity.
David, thank you so much for joining us today. Your contributions to wound healing have been tremendous. Not only have you provided daily reminders of how data can drive care because of the things you’ve developed that are being used in clinical practice today, although you hope that someday maybe they won’t have to be used, you’ve also trained a generation of people who will carry on the work.
With great gratitude, I want to thank you for joining and also thank you for your contributions.
Dr. Margolis:
Thank you for having me and for saying all those kind things. I’ll have to save this recording for when I die, so at least I know that there would be one kind thing.
Outro:
The SAWC Difference Makers Podcast is brought to you by the Symposium on Advanced Wound Care, one of the leading forums for advancing wound care education, research, and collaboration, and by Wounds, the official journal of SAWC.