[00:00:00] Speaker A: Foreign.
[00:00:15] Speaker B: Welcome to the Few and Far between podcast. I'm your host, Chris O'. Brien. So where did CROs come from? The original concept began in the 1940s with the 1980s seeing the first official CRO, but what about the points in between? Who pioneered the study protocols, recruitment plans, and data analysis that we still use today? My guest today is one of the deans of the clinical research industry, a clinical scientist who finds beauty and art in protocol development. Dr. Mark Abelson is the founder of Oura, Inc. The world's leading full service ophthalmic clinical research firm, boasting 38 FDA approvals. On today's episode, Dr. Abelson and I will travel back to the beginning. From his Start at the McGill University School of Medicine in Montreal, to his specialization in the cornea program at Harvard, to to building one of the first CROs from scratch. We'll also get a chance to take a deep dive into the body's mast cell and its role in inflammatory triggers, the importance of learning from failed clinical trials, and how parking might be the essential factor in choosing a clinical site location. This episode was a lot of fun and really informative. I hope you enjoy it. Okay, let's start the podcast.
Mark Abelson, welcome to Few and Far Between. I have been looking forward to this conversation.
[00:01:34] Speaker A: Thank you very much. Great to be here.
[00:01:36] Speaker B: So, you know, I think it's fair to call you one of the deans of the clinical research industry. You didn't intend to start a CRO, though, early in your career, I think. Tell us a little bit about how you got started in medicine.
[00:01:49] Speaker A: I went to medical school.
[00:01:51] Speaker B: What did you think you were going to study as you were coming out of medical school?
[00:01:54] Speaker A: Well, it's sort of interesting for the discussion we're going to have if we take one step back and look at undergraduate training. I was absolutely fascinated with the experimental psychology. It proved to be very helpful many years later, learning how to write a protocol, analyze data, look for flaws in a study, look for a signal.
[00:02:17] Speaker B: Oh, that's fascinating. So you kind of learned the trade initially in social science.
[00:02:21] Speaker A: I learned it in physiologic psychology at McGill. It was quite well known for that. And I really liked, I guess, the science. I liked designing a study to find out an answer and init, of course, the subjects were all rodents and rabbits and et cetera, but some, some humans then going to medical school, I thought initially from psychology to psychiatry. But you know, most of the patients were crazy. So I, you know, I don't. If you have to bleep that out. I don't mean that.
[00:02:54] Speaker B: No, we, we're comfortable with crazy as. I think the percentage of crazy patients in psych is probably higher than the percentage in any other field of medicine. I think that's the same. A safe assumption.
[00:03:02] Speaker A: Well, it's crazy scientists as well. Exactly.
[00:03:05] Speaker B: It's not zero anywhere else.
[00:03:06] Speaker A: In medical school, I was very interested in physiology and have been and still am, and how the body works, how the heart works, how the blood circulates. So I started out part of the internship in general surgery and cardiovascular surgery. When it came time to pick a residency, I found that Cardiac surgery, General surgery, they stayed up late, they spent a lot of time in the or. Made me very tired.
[00:03:33] Speaker C: Fair.
[00:03:33] Speaker A: And actually, you know, in terms of a story, I was walking down the hospital corridor and I saw this gentleman sitting at his desk in an office. The door partly opened and he was having a cup of tea at 8 o' clock in the morning. Okay. Every surgeon was already been in the OR for an hour and up for three. So I walked in and I say, excuse me, sir, what is it exactly that you do? Just. Well, I'm the chairman of the department of ophthalmology.
[00:04:00] Speaker B: Fantastic.
[00:04:00] Speaker A: Oh, it's funny you should say that. I want to be an ophthalmologist.
[00:04:05] Speaker B: A decision reached in that moment.
[00:04:06] Speaker A: Yeah, it seemed like a very gentlemanly field.
[00:04:11] Speaker B: I love that. Okay, so you decide to go into ophthalmology and eventually you end up with a fellowship at Harvard. Is that kind of how you got to Cambridge?
[00:04:20] Speaker A: Yeah, I finished my training at McGill, Department of Ophthalmology. And being from Montreal, and at that time McGill was probably one of the best medical schools. And so it all worked well. And I did basic science course at Stanford, met mate Allen Smith, who was the first ocular immunologist allergist. The field was brand new.
[00:04:43] Speaker B: Yep. Okay.
[00:04:44] Speaker A: And those of you who may share my age recognize that in medical school immunology was a two hour course.
[00:04:51] Speaker B: It's fascinating.
[00:04:52] Speaker A: And so I worked with her and Klaus Doleman in Boston, the Mass Eye and Earth, and was able to continue to do some of the research. I started as a resident trying to understand cornea transplant rejection, ocular allergy, and some of the immunologic diseases of the eye that we didn't even know were immunologic back then. And so my interest in the Harvard cornea program, you had to have a basic research interest. And mine was the mast cell, which to me is and still is one of the most fascina Cells in the human body contains upwards of 100 different mediators, each reflected by a different crystalline structure in this flickering cell. And I became interested in it, particularly because it seemed to contain histamine. And I became interested in histamine, antihistamine, histamine receptors, mast cell distribution with mate Allen Smith, and then those diseases like vernal conjunctivitis and allergy that were based on the function of that cell. Now, the mast cell is a fascinating cell. It's very important in allergy and plays a critical role in homeostasis, controlling various blood vessels and pools of capillaries. By releasing vasoactive amines, it also releases chemicals that help trigger and modify the entire inflammatory response. So there was enough to study there and kept me interested, and still does to this day. And I'm still very interested in how it causes dis and how it can be modified. Now, this became pretty important as the story unfolds. Unbeknownst to me, I just was interested in the mass cell because it was incredible.
[00:06:41] Speaker B: Yeah, yeah. What was the feeling like at that time was the sense that you guys were. You were charting new territory all the time. You know, that amount of discovery, the pace of discovery and exploration was faster than maybe it had been a generation before. Faster than in the future, or do you think, no, no, no. It's stayed kind of constant over your professional life?
[00:07:00] Speaker A: That's an interesting question. At the time, it seemed like there was so much unknown, so much still to do, that plying.
Some of the early assays for inflammatory mediators, including histamine, had not been done in the eye. So it was like the field was fully open. Anytime you did a study or an assay was new and interesting information.
[00:07:21] Speaker B: Yeah, exactly. That's gotta be incredible.
[00:07:23] Speaker A: Yeah, it's great fun. What you're doing, you can see is meaningful. And if I could bring up the term clinical scientist, because that's the product that the Harvard Mass Eye and ear program was producing in each of the specialties. Someone who was working in the lab with cells, with animals, histology, trying to understand basic mechanisms, was also spending part of their time in the clinic seeing patients, treating disease. Matching those two things together, seeing the dise, seeing how little we understood about it, and then either trying to create a model of the disease or assaying the patient for presence of various chemicals. Mediators that could be causing the disease were the focus of the clinical scientist. And a full couple of generations of clinical scientists have played an incredible role in elucidating a lot of the Mechanisms that underpin our understanding of disease today. That's where it came from.
[00:08:24] Speaker B: And Mark, you believe, I think, that that link between seeing patients and then actually also being in the lab, it was that combination that was really powerful. Is that right? And if so, did you feel that was unusual at the time? It seems like it must have been.
[00:08:39] Speaker A: It was very powerful. You were seeing the patient in an additional dimension. Yeah. Not only clinical signs and symptoms, demographic progression, epidemiology, response to therapy, concomitant disease, all the parts of the clinical aspects, but you were also seeing as what is the cells and what are the mediators that are impacting on what specific tissue? And what is the. Is there a key mediator, a chemical that's driving this process that could be modified? Can we assay for it and then can we treat for it?
So, yeah, it's the core, and I would say to be a clinical scientist, do a fellowship like this, you already were a licensed ophthalmologist, and if you wanted to be a specialist, that was fine. Learn how to do a retina, learn how to do a cornea. However, this was another year at a time when many people had rung up a lot of expenses or were anxious to get out and practice and to spend a year in the lab at that time when many people were, you know, ready to get out there and use their clinical skills. So it wasn't a large group that did the research part of it, of course, it was a large group that did the specialties in glaucoma, plastics, pediatrics, et cetera. But matching that with the lab was not that frequent then and unfortunately is even less frequent now because of the. There's less funding, there's. The economics of practice don't allow you to practice three days a week and do research for some nominal fee the other couple of days. And certainly I've been very supportive of clinical research program. We support a family fellowship in clinical research at Harvard, the same one that I was part of, because I believe that's a critical part of our future. And hopefully that'll continue to exist and hopefully funding and focus will increase so that it resumes its important role that it has played. And whether this information is to better understand the disease or be able to pick a drug that can work in the disease, or tying everything together. We'd say design the study based on how to design a protocol, proper statistical methodology, proper patient selection, using the subjects that have the particular disease characteristics you want to study or modify. All of that is really the core of our future in drug development and the future of ophthalmology in general. And having these skills are absolutely critical.
And the people who have these skills, and there are a significant fortunate number of them today who are driving the science forward. It's become far more commercial than it was. We now have companies that only do statistics, only do recruiting for studies. CROs do the monitoring. Regulatory groups that interface with the FDA to determine what an appropriate endpoint or scale is that'll define an acceptable and meaningful clinical transformation that can be the pathway for a new drug.
So there's many components of the system. Ones that really drives it is someone who pulls it all together.
[00:12:08] Speaker B: Yeah. Synthesis.
[00:12:10] Speaker A: And has a finger in each of those parts. And that's often today called key opinion leaders, KOLs, medical directors at pharmaceutical companies, or specific CROs that are skilled in a particular area, whether it be oncology, ophthalmology, neurosurgery, etc. So it's a huge ecosystem that's grown out of what used to be just one person.
[00:12:37] Speaker B: That's right. We've moved into a specialist world.
Hi, this is Chris o', Brien, host of Few and Far Between Conversations from the Front line of Drug Development. We'll be right back with this episode in a moment. I personally want to thank you all for listening to our podcast. Now in our fifth season. It continues to be an amazing opportunity to speak with some of the top thought leaders in the drug development industry. If you're enjoying this episode, please leave us a review on Apple Podcasts. It really helps people discover the pod. And don't forget to subscribe to Few and Far between so that you never miss an episode. One last request, know someone with a great story you'd like to hear me interview. Reach out to
[email protected] thank you. And now back to the podcast.
Let's go back to that one person. So talk, if you will, about Andover.
[00:13:33] Speaker A: I.
[00:13:33] Speaker B: In the beginning of your deciding that to build a business here, or I don't know if that's the right verb to use, did you decide to do it or did it just kind of happen and evolve?
[00:13:42] Speaker A: Well, there's two things you said that are interesting. Decided and business.
[00:13:46] Speaker B: Yeah, okay. Right.
[00:13:47] Speaker A: I can talk to both. First of all, business. Never really saw that this could be a business. It wasn't. I just was interested in doing studies on patients who initially had allergy to better understand it. And then did I ever have a plan? No, none at all. Because what I built didn't exist.
And at the time I started, we would go literally for years, years without a new drug approved prednisolone, steroid, and then the antibiotics like Neosporin and then a combination Cortisporin were hallmarks of the therapy in the late 60s and 70s. And then the aminoglycosides and in glaucoma, it was Pilocar, had been used forever and that was still a primary therapy. So the pace of understanding of disease and drug development picked up very quickly in the 80s, 90s, and certainly in the last 20 years. It's hard to go a month or two without a new drug being approved. And some of them are transformational, others are less expensive, safer, more comfortable. But occasionally, and more frequently than ever before, we're getting drugs that are transforming our ability to treat patients with wet amd, patients with thyroid ophthalmopathy, dry eye, and on and on. So it's been a, as you indicated, for a rapid improvement in the quality of products and the speed with which they're developed. Now, going back to your question, I didn't see it as a business. I was really interested in doing it. And I was working on my mast cell and allergy in Boston, and I really had trouble finding subjects, patients to come in for a study. Those of you who've done studies in hospitals know it's difficult getting clinic time, getting staffing regulations in the days when I started predated computers, of course. And everything was in a file in the basement somewhere. And you can imagine the Mass General, Mass Pioneer, that was hundreds of years old. There's a lot of stuff down there.
[00:15:56] Speaker B: Right.
[00:15:57] Speaker A: It was a miracle that they found the files.
And so. And patients didn't want to come. There was part the park didn't want to come to be subjects. So when I, when I was starting to look at the effects and to assay for samples in subjects, it didn't seem that the Boston location was a good place. And Klaus Dolman, my mentor, suggested, why don't you go into a suburb and open a practice like a half day a week and transform those patients into subjects. Parking will be easy. You'll have their records. There's more of an interpersonal relationship, staffing, etc. So for those reasons, I opened up Bando Bry Associates, really as a clinical site for subjects.
[00:16:42] Speaker B: I love that parking was an essential factor in this important chapter in your life and career. Makes sense.
[00:16:48] Speaker A: It's all about parking.
[00:16:49] Speaker B: Yeah. Yeah. Boston parking's a nightmare. Yep.
[00:16:52] Speaker A: Then it grew as a practice, and I brought in a number of fellows from the Mass Eye and ear in retina, plastics, glaucoma, et cetera.
And built. And studies. We did some studies.
The studies increased in number and staff increased, and then the whole industry, drug development increased. So it took on a life of its own, more than I really ever had imagined. It didn't exist as a career I would have chosen when I started, but it became something that I was very interested in, in helping to get drugs to market and I participated in. I guess at this stage, the number is 85 drugs and devices that have been approved.
[00:17:31] Speaker B: Yeah, that's an extraordinary 8.5 would be a pretty impressive number. 85 is extraordinary. Really?
[00:17:37] Speaker A: Really. Well, the corollary was I did it over 45 years, so it's not that much if you spread it out.
[00:17:44] Speaker B: Yeah, that's true. It's true. You paced yourself, you're back to.
[00:17:49] Speaker A: You're back to one or two. That's sort of how the clinical research morphed out of the lab effort, really. I guess morphed out of the clinical specialty of cornea external disease. I mean, I've always been just absolutely fascinated by how all of us are, how the body works and physiological systems, you know, what triggers tearing, what are its components, what happens when histamine is released and how does it interact with histamines. And what are the roles of chronic allergic diseases, drug allergies, vernal conjunctivitis, atopic keratitis, all those conditions that really we didn't understand or had no treatment for.
And for all of them now we do. In allergy alone, I help get 16 drugs approved. They're. They're pretty well, mostly over the counter now, but they've transformed how patients are treated. They're widely used throughout the world. And that's sort of a nice thing to see.
[00:18:52] Speaker B: I bet, I bet. So, you know, I guess if you were a young person embarking on your career, you would have hoped that you would have a role exactly like what you just described, that you'd be involved in developing or bringing to market a bunch of different drugs and devices. My guess is you wouldn't have maybe thought 85. Maybe you would have thought a smaller number, but you would have hoped that you'd do something like that. But you also were part of kind of the development of the professionalization of clinical research.
[00:19:20] Speaker A: Right.
[00:19:20] Speaker B: I mean, when you began, did people know what an SOP was or, you know, what?
[00:19:25] Speaker A: I didn't.
[00:19:26] Speaker B: Yeah, right, right, right, right. Nobody did.
[00:19:28] Speaker C: Right.
[00:19:28] Speaker A: Early on, I had this company come to me and ask if I would do A drug study on Vasocon A, an antihistamine vasoconstrictor, because the FDA wanted proof that it worked. I had no idea, you know, I know, yeah, I'll put the drug in one eye and see what happens. What a protocol would be like going to the fda. What, making sure that it was manu. Manufactured sterile and safely. All those things I had no idea about. And they said, well, for clinical, you know, doing a clinical study. Could we see your sop?
[00:20:03] Speaker B: Yeah, yeah.
[00:20:04] Speaker A: I said, my what?
[00:20:06] Speaker B: Times have changed.
[00:20:07] Speaker A: And so, yeah, this was long enough ago that I could say, so it was a study with Allergan, and they were just starting out and they said, well, yeah, no one said, we have some. We'll give you our SOPs. Just cross out our name and put yours.
That was our first SOP and the training and certification of each member of the staff. Now there are professionals, clinical research associates, data management, study managers and coordinators. It's become obviously an industry, but it wasn't. It really wasn't. It was a doctor who might have been interested in something with his secretary or nurse.
[00:20:51] Speaker B: Yes.
[00:20:52] Speaker A: Doing a study on some of his patients as they came through on a mimeographed. I don't know where you've heard.
[00:20:58] Speaker B: Yes, I form. Yes, I remember. I remember mimeographs, but I'll be honest, I was a little kid at the time.
[00:21:04] Speaker A: And so the industry just has transformed as patients expectations for better therapy as our knowledge increases. I think, you know, I don't have numbers, but the number of drugs that were available 50 years ago has got to be 10% of what's available today. And that's a very important process. And we got to make sure that process continues and that we fund and support the clinical researchers and we support some of the basic science, at least to our understanding of mechanisms. Is one of the things I was always very interested in is if I had to do a study on allergy and I couldn't always find the patients who were allergic. That day I was doing the study, and I was doing a study for ragweed in the middle of ragweed season on a weekend advertised everywhere. We had 50 ragweed patients out there. They were told to just come on in as soon as their eye got a little red and itchy. And so we sat there all weekend. I think it was three or four of us. I think two people came in and said, okay, this isn't going to work.
And that led to the establishment of the conjunctival allergy challenge was to control the creation of models, and this was the first of a number of models to create the disease right there. And it was the disease, because clinically it had the signs and symptoms of that disease and not of others. And it also had mediator or cellular confirmation that was similar to seen in the disease in the wild. So the conjunctival antigen challenger cac, where you'd put pollen in the eye and produce the allergy right there in the chair, and then you could treat it and see the effect. Drug versus placebo, right eye versus left eye, or baseline versus drug, or group A versus group B, depending on how.
[00:22:52] Speaker B: So was that in hindsight, that feels like an obvious answer, like lots of good ideas. Was that something where people said, we need to do this all the time, instead of waiting around, let's find ways to use that across different therapy areas, disease states, et cetera. Or did it take a while for that model to concept, to get it to sort of spread?
[00:23:11] Speaker A: You have two parts to the question. Very good. One is the concept of creating or stressing the system. Yes, if you look at what we do for cardiac stress tests, so we do that. There are certain tests, they do respiratory tests and asthma. But this was designed to evaluate drugs and was accepted widely. Actually, the refinements of this I did with the FDA and the paper on this, I think the early 80s, was with Wiley Chambers, the head of the FDA.
So it became an acceptable model and led to the precise definition of how a drug works, is time of onset, duration, and comparing drug A to drug B for the signs and symptoms of ocular allergy. So this represented a very simple, useful, clinically relevant, pathologically correct model of the disease.
And we then went on and did the same thing in dry eye with a chamber that produces a controlled airflow, cubic feet per minute, controlling for temperature, humidity, to try and dry out the eye, to determine the effects of drugs to either block or reverse damage produced by a drying environment.
Because similarly, dry eye people differ from each other to a great extent and they almost differ within themselves. Seasonality, time of the day, just other random factors. All the stuff that gets in the way of doing a very precise clinical trial to define a drug effect.
So if you can produce the condition and you have a time of onset, you can compare, just as we discussed with allergic drugs, you can compare the effects of dry eye agents. And just as I would say, I was involved in the development of all the allergy drops, certainly all the dry eye medication as well, certainly involved in, from endpoint scales, models, protocol development, Data analysis or execution or all the above.
[00:25:18] Speaker B: Mark, it's pretty obvious we gained a lot from this professionalization, systemization of the clinical trial process, the development of these niche areas of expertise. Are there things we lost in that process or do you view it as just a set of gains?
[00:25:33] Speaker A: I don't think we lost anything. I think one could say, well, I could. If I wasn't doing research, I could have done more cornea or anterior segment surgery maybe, or seen more patients, but they seem to all get seen anyway.
[00:25:50] Speaker B: Yep.
[00:25:51] Speaker A: And I really, you know, I just could not sit in the office and see patients five days a week. Greatest respect for people having excitement for clinical work in and of itself, that they find that motivation and those are critical parts of our healthcare system. Yes, but that wasn't something I felt. I just had questions I wanted to answer. Maybe, you know, I could say yes to help every patient. Really, just questions I want to answer. I was interested in the answer.
And, you know, how did this mediator produce these signs or symptoms, produce that disease? It was just an absolutely thrilling adventure and still is.
[00:26:31] Speaker B: That's fantastic. Like, you said different things for different people. A quote that I think you said when we were prepping. You said that protocol development is more of an art form than a science. Will you talk about that a little bit?
[00:26:43] Speaker A: Yeah. I think obviously there's the science. It has to be structured.
Obviously, patients have got to be selected in a way that there's no bias and have to be randomly assigned to various groups. All data has got to be collected objectively and reproducibly and analyzed in a way that compares the positive effects to other aspects or severity of the disease and also tracks very precisely any adverse events. All of that has to absolutely happen. But when you design a study, is it a crossover design?
Is it a drug incremental aspect to the study? Are you challenging them? Are you controlling for the time of the day you see them? Are you using new scales, new endpoints that more reflect the precision needed in this type of endeavor over being in the clinical office. A protocol is certainly a creative process and a beautiful protocol. I mean, I see it as an art form, answers all those questions. It's, you know, the ultimate. When you do a study, you want to control for everything except what you're testing, the one variable you're testing. And it's often not possible, but the ways you go about trying to make it as precisely controlled, because you talk about controlled studies, and for each disease and each drug, each subgroup, protocol has got to be modified. There's no real good off the shelf unless you're doing a me too drug that's already been shown effective. You want to keep everything the same. There's often opportunity in a protocol to do what's called exploratory endpoints. And that is you may want to test, let's say you want to measure shoe size. It doesn't seem relevant, but you may feel that that has a role or, you know, myopia. Now people are interested in the sclera and sclera thickness. Does that have any relevance? And collagen in other part of the body. So you have an opportunity to be creative and select not as a primary endpoint will get the drug approved, but may help you understand how the disease of the drug works in this. You know, because each of these studies are millions of dollars. Yes. And it's an opportunity once you're doing it, to gain information about the disease as well as the drug. And as a clinical scientist, you sort of. Those are the two things you want to. When I finish a good study, I want to know how the drug worked and I hope I know more about the disease.
[00:29:13] Speaker B: Yep, makes sense. Mark, what advice would you give to somebody who's starting out in that journey of sort of building protocols? Are there general suggestions you can make for how to get better at that, how to think about that stuff?
[00:29:25] Speaker A: I think a lot of it is to read studies. You learn most by reading studies that have gone bad.
[00:29:32] Speaker B: Yeah, right. Great idea.
[00:29:33] Speaker A: Where something wasn't the result. Actually we see them all the time. If you look at studies that show that, for instance, visual loss in with WeGovy, there are six or seven studies and three show there's some ischemic optic neuropathy and three or four show there isn't. And so the question is, if you read those studies and look carefully into it, try to understand how the study design led to that result. And was there a built in unacknowledged bias that accounted for what you're seeing? Were the patients selected from a subgroup with a higher incidence of that condition? All the things you need to control for but you learn by just reading read protocols. And where do you find them? You find them in all the journals. They're the part of the article that you don't read.
[00:30:23] Speaker B: Right, Right.
[00:30:24] Speaker A: You go to the result.
[00:30:26] Speaker B: Yeah.
[00:30:27] Speaker A: How about you read the middle of it? In there is how a protocol was done and you may say what? Or wow, that was a good idea. And it's sort of like the middle of a banana. That's where that's where the action is.
[00:30:41] Speaker B: That is not an analogy. I expected the good of the protocol or the good part of this. The article is the middle of the banana, but I like it. I like it. So, okay, so read lots of protocols. And especially to your point, read protocols from failed studies because if you can identify what went wrong or what the person didn't account for, you're saying you learned one more thing to protect against when you're writing your own.
[00:31:01] Speaker A: And this is still an area in our field that not enough effort goes into. There's still a tendency to go off the shelf on a protocol. Either a fear of deviating are being driven by pharmaceutical companies who are maybe overly risk adverse. And it doesn't mean you can't do a traditional protocol, but you should always be trying to find something new. Clinical scientists should be looking for a new endpoint or a new scale, a new time point or a new way. Let's say you're interested in what's called a condition where they wake up with red eyes in the morning and swollen lids. Morning congestion syndrome. Well, that's something that they wake up in the morning with and by the time they get out of bed and become dependent, the lymphedema decreases.
So you want to get them while they're lying down. We did a study where we kept people in a hotel room and we would go in and get them out of bed after we took a picture.
We've worked on a modification of, of the iPhone that can be used at home. It has a cone that controls for distance and illumination and the patient can take the picture himself. So you don't need the hotel and you don't have to be there in the morning. Thank goodness. So technology also can help in areas like that. And then also assays keep increasing. How much can we measure in a biopsy or impression? Cytology, tear collection, mucin analysis, these all help us understand. And I'm talking a lot about external disease because that's my field. But I'm also very interested in the psychophysiology that's developing for macular degeneration, dry amd. I mean, number one, cause of blindness, what are the earliest indicators of it? We talk about visual acuity, visual function, like 2020, but visual function is color vision, contrast, fix and follow. There's a number of other more complex visual functions that actually occur at the level of the retina that can be impacted by early amd. The question is, can you find a test or a series of tests that can predict that this person, even though their vision is 2020 and their retina looks pretty good, they're already missing a visual function. And this is an area that's very ripe. And I'm interested in right now because we got to select that subgroup of people when the AMD drugs come through. Now we're starting to get dry amd, we have wet AMD drugs, we have approvals for geographic atrophy. But what about when the retina, you know, where it's going to be just macular degeneration without the peripheral atrophy and it's going to be detected only when there's enough damage to the macula and the vision is worse than 2040. What happens before then? A very ripe area for clinical research that'll dovetail into better understanding the disease, getting drugs approved and treating. And often the clinical scientist has got to be a frontrunner and create these tests, scales, endpoints to help drive the.
[00:34:10] Speaker B: Field forward, Mark evidence or the examples you just gave us. You still have a busy research agenda. There's a lot of stuff that you're still interested in, but you've also been doing this, you've been doing this for a while, as you pointed out. What advice do you have for people who are early in their scientific careers, in med school and grad school, etc. Life advice and or medical advice.
[00:34:31] Speaker A: Follow your heart, of course. Do what you love. And if you do something you love, obviously you're going to do it well and you're getting positive feedback early on. Building a career, success.
You chase success, you may end up with nothing. But if you chase doing something you love and are chasing a problem, it could be a disease. It could be a series of receptors or physiological feedback loops in kidney, in the eye, wherever. If you're excited to find out how this works or how it can be made to work better or how it fails, that's just a wonderful lifetime puzzle mental challenge career that'll get you up in the morning or awake at night. What about this? What about that? If you focus on that and if you're fortunate to have a. And certainly it can happen through the PhD side, but I'm a proponent of an MD with research training, either as an MD, PhD or an MD with a clinical fellowship, which is probably even more relevant, and just keep your head down and do good work and everything else will happen, but along the line it's going to be a blast.
[00:35:45] Speaker B: That's fantastic. There's one, one that you said to me the other day that I want to close on, that involved Your grandkids and thinking about them when you're. When you're making decisions. Do you know what I'm thinking about that? You said, you mind sharing that?
[00:35:56] Speaker A: Oh, I think that came out of your question about legacy.
[00:35:59] Speaker B: Yeah, okay. That's fine.
[00:36:00] Speaker A: Really.
It doesn't resonate because you're not there anymore. But your real legacy is your grandkids. Your progeny can point the way that they can follow or give them an option to select a career or a process for selecting a career that is joyous. So I think that's one thing. I think the obviously legacy. Lots of people use drops that I developed. That's very nice. But it's sort of nice for grandkids to know that their grandfather played a role in the development of this eye medication, even though it's probably by then it'll be old and no one's using it anymore. I guess I look at legacy very close to home like that.
[00:36:43] Speaker B: Yeah, I love that I'm leading the witness, but one of the things you said that really struck me was you suggested that even young people can think about doing things that would make your grandkids or future grand grandkids proud of you. I liked that as a frame that probably most people, young people certainly, but even, you know, my kids are grown, but I don't have grandkids yet. So I. I don't think of future grandkids and their point of view on my life, but maybe I should.
[00:37:06] Speaker A: I think you should, and I think everyone should. And I think even your kids think of their grandkids.
[00:37:12] Speaker B: Yeah, right.
[00:37:12] Speaker A: In other words, can you live a meaningful, exemplary life, make contribution and point the way for them to do that? I think that's a life well led, Mark.
[00:37:21] Speaker B: I think we'll leave it there. I don't know how we could come up with a better final line. You are certainly in the process of leading a meaningful and well lived life. Thanks for taking some time to talk to me today.
[00:37:30] Speaker A: It's been great.
[00:37:34] Speaker B: Welcome, producer Adam.
[00:37:36] Speaker C: Thank you, Chris. So it was great to get a new perspective on the beginnings of the CRO industry in this episode. Dr. Abelson seems to be like he was really on the front lines. Did his role as a trailblazer inspire you a little bit?
[00:37:50] Speaker B: It really did. I mean, I had thought before about the entrepreneurial spirit that goes into starting a CRO. We see that at our own company, Biorasi, and we've seen it at others, but the idea of inventing the whole industry, which is really what he's talking about. And not that he's claiming credit for full invention, but a lot of things that we take for granted and how we run studies today. Yeah, none of that stuff had been figured out yet. When he first started working running trials, they were inventing it as they went along. I think the processes as well as the technology have come a long way.
[00:38:18] Speaker C: Yeah, you know, I'm going to get back to Bio Rossi as a CRO in a second. But one of the things that impressed me the most, I think, is his creative process and the belief that study protocols are true art form.
[00:38:30] Speaker B: Yeah, I really loved that as well. I think a lot of times truly innovative people see their work as a creative outlet, and I think that's what he was describing.
He's a really compelling guy and thus still active, and thus all of these drugs he's been involved with bringing to market. You know, you and I have talked about that before, that we've had people on the podcast who've had, you know, one drug approval or seeking to have one in their career. We've had a few who've had a handful or a double handful. I don't think we've ever had anybody on who's been involved in as many approved drugs as Dr. Abel said. Yeah, he was not at all. He was really a gem.
[00:39:01] Speaker C: So, yeah, back to the creative process, I guess he was talking about adding exploratory endpoints to studies. Is that something that is still. Still common in today's clinical trials and people are still have the ability to do that?
[00:39:13] Speaker B: Yeah, I would call it a mildly controversial point. Certainly there are people who think you should be extremely disciplined in the trials. You structure and, you know, one of the distinctions I've heard people make is that academic scientists will tend to say, hey, it would be fun to learn this, or it'd be interesting to learn that. Whereas the world of biotech is about. We want to be very focused on a primary endpoint that we believe advances the drug or device through the clinical trial process. And I kind of like his idea of, yeah, yeah, yeah, we should do that, of course, but let's look for ways to learn more as well as we go through the process both to advance science and to expand our understanding of the possible with compound or device that we're developing in this particular trial. So I thought that was great and a helpful antidote maybe to the. Or alternative way of thinking to some of the other stuff that we hear.
[00:39:58] Speaker C: So one of the other things that we talked about was the importance of learning from failed clinical trials, which is something that we've discussed, discussed on the pod with a lot of our guests in the past. In the current state of the industry, based on policy changes and the economy, is this still a viable direction for biotech?
[00:40:14] Speaker B: Yeah. Yeah. Well, I think it's probably pretty hard these days for a CEO to come back and say, you know, it didn't work, but, boy, we learned a lot. It was all about the journey. It's probably not a great conversation for a biotech CEO to have with his or her board. On the other hand, that is the process of discovery in any industry, but especially in biotech, where you have so many failures before you get to success. And I think one of the things that makes the US Biotech ecosystem so powerful is this tolerance for failure. So that's not tolerance in the moment. I think people are still going to be frustrated and disappointed if a study fails, of course, but sort of over the course of a career. What we're trying, we're all trying to do is to learn from the things that didn't work last time so that we can get a little better next time. And I think the industry, broadcast broadly, does have a view that, okay, well, if the last thing you didn't do didn't work, that doesn't mean the next thing won't. And in fact, you've learned some stuff in that process. So I guess over the long scale of time and over careers, there is still tolerance for that, I believe. But, boy, it's a tough funding environment right now. So coming back and saying, golly gee, we learned a lot, and it was all about the friends I met along the way is probably a tough conversation.
[00:41:18] Speaker A: Right, right. Yeah.
[00:41:19] Speaker C: I'm gonna agree with you. That's not a conversation you want to have of. So I'm going to put you on the spot. You know, as the CEO of Biorossi, how do you balance its legacy and the future to create a successful company?
[00:41:32] Speaker B: That's a really tough question. I think any CEO who is honest would say that we all struggle with that, that the combination of honoring what came before, but not being a prisoner of the things that have worked in the past, especially in an environment where we're seeing so much change right now, and that's change at the regulatory level, it's change at the societal level, and it is change at the technological level. So, you know, the way in which we conduct clinical research in a couple of years is likely to look pretty different than the way that it looked in the past. So I think, you know, as a CEO Your job in part is to think about what are the things that distinguish your organization and how can you double down on those. And a lot of that comes down to culture because think of some of the tools changes as time goes along. But you want the, I think you want the essence of the company to remain, you know, the compass direction to still be pointed at the direction that it was pointed at in our case. That's supporting world class science and helping to bring these drugs to patients.
[00:42:27] Speaker C: All right, it was a really interesting episode.
[00:42:30] Speaker B: So yeah, what an incredible career he's had and what an interesting conversation. Lots of fun. Thanks, Adam.
Thank you for listening to the latest episode, Few and Far Between Conversations from the Front Lines of Drug Development. Our podcast is now available on Apple Podcasts and other streaming services. Please take a moment and leave us a user review and rating today. It really helps people discover the podcast and we read all the comments. Those comments help us make Few and Far between better and better. Also, be sure to subscribe to Few and Far between so you don't miss a single episode. Got an idea for a future episode? Email us at fewandfarbetweeniorossi.com or contact us on our
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