Complexity in Early Phase Clinical Trials with Dr. Oren Cohen

Great clinical research professionals aren't born, they're built. In each episode, here from leading experts in clinical trial management, as they inspire and motivate you to become an effective leader. Welcome to the Clinical Trial Podcast. Here to help you accelerate your career is your host, Kunal Sompat. Hi friends, welcome to another episode of the Clinical Trial Podcast. Where my job is to help you accelerate your clinical research career. When a new drug or device undergoes first in human experience, the primary focus is patient safety. How will the drug or device interact with the human body? And will this interaction be safe? To answer these two questions, regulatory authorities around the world require medical product manufacturers to conduct phase one, also known as early phase clinical trials. To learn more about the complexities of early phase clinical trials, I invited Dr. Orhan Cohen, president of clinical pharmacology services and chief medical officer at Lab Corp Drug Development on the show. Dr. Cohen has more than 30 years of health care experience which includes his work on clinical development. Prior to joining Lab Corp Dr. Cohen served as chief medical officer at Vinemit Pharmaceuticals. He has also helped multiple leadership roles at Quintel's Inc. such as senior vice president global head of early clinical development decision medicine, senior vice president clinical research strategies, vice president and senior director medical and scientific services among others. Dr. Cohen received his MD from Duke University and completed his internship and residency at the New York hospital Cornell Medical Center in New York City. He completed his infectious diseases fellowship at the National Institute of Allergy and Infectious Diseases and IAID and stayed on to become an investigator in the laboratory of immunoregulations where he conducted basic and translational research under the supervision of Dr. Anthony Fachi. He also served on the National and Director of Viral Guidelines panel and ultimately served as the assistant director for medical affairs for the NIAID. Dr. Cohen has published scientific papers in Science the New England Journal of Medicine, the Lancet, the Journal of Clinical Investigations and Proceedings of the National Academy of Sciences among others. He is a fellow of the Infectious Diseases Society of America and a consulting professor of medicine at Duke University Medical Center. Please join me in welcoming Dr. Cohen to the Clinical Trial Podcast. Dr. Cohen, thank you so much for joining me today on the Clinical Trial Podcast. It's really a pleasure to have you on the show. I think people are just going to be really pumped to learn and grow and learn about early for its clinical trials and the complexities around it and there's no better person than you do kind of share with us what all of this entails. So thanks so much for accepting that invite. My pleasure, a great to be with you. Really, really pleased to have this conversation with you. So Dr. Cohen, maybe we'll start off with your role as a Chief Medical Officer and President of the Clinical Pharmacology Services at LabCorp. Just for background purposes, can you tell us what role does your division or department play as it relates to early phase clinical studies? Sure, I'm very happy to. So interestingly, lots of mergers and acquisitions in the CRO industry over the last number of years. And co-vance was a drug development CRO, which was acquired by LabCorp probably seven years ago. And that part of LabCorp is now known as LabCorp Drug Development. So the overarching LabCorp umbrella is now comprised of LabCorp Diagnostics, which is the health care diagnostics part of the organization, as well as the drug development organization, the CRO, which used to be co-vance. So the early phase drug testing organization that I oversee is comprised of four phase one clinics, three of those in the US in Daytona, Madison, Dallas, and then one in the UK in Leeds in the north of England. I see. So these are basically these four units are phase one clinical trial sites. Is that what they are? Correct. These are clinical pharmacology units that specialize in phase one clinical trial. I would say that the model has changed a lot over the last five years or so. We used to think about phase one clinical trials as exclusively conducted in normal healthy volunteers in phase one clinics like these. That model has shifted a lot as phase one clinical trials have become a lot more complex. So there's a lot of interdependencies. We conduct phase one clinical trials often in multiple phase one clinics now. We conduct phase one clinical trials in external sites that are external to our own four clinical clinical clinical pharmacology units. We conduct some of these trials in patients at university sites and highly specialized sites. So it's a much broader network that we need to conduct early phase clinical research these days. I see. And what's the reason for selecting multiple phase one sites or external sites? Yeah, it really is the complexity that drives this. And, you know, I would say that 10 years ago, the norm in phase one clinical research would be to do a single ascending dose study. And when we get the results of that single ascending dose study and then move into a multiple ascending dose study and get the results of that and then move into the next study, it was really a very spaced out process sequential process. These days, you know, the pressure is to really accelerate development and get results much faster, get results not only with regard to safety and pharmacokinetics, but, you know, get hints into pharmacodynamics is the molecule interacting with the target in in an expected manner. And is there a biological effect that is anticipated? You know, to have a biological impact that's anticipated. So that's driving unprecedented complexity in trial design. And so frequently these days, we see clinical phase one clinical trials that are hybrid protocols that are combination single ascending dose multiple ascending dose food effect drug drug interaction. Plus a cohort that involves Asian ethno bridging and the final cohort in patients with the disease that the drug is intended to treat, for example, all in one protocol. Whereas in the past, that would have been many separate protocols spaced out over a much longer time period. And, you know, that complexity forces us to leverage a lot more than a single clinical pharmacology unit. It's really keeping up with that complexity that that forces us to really leverage a whole integrated development platform as we call it, rather than just the four walls of the single clinical pharmacology unit. I use the term clinical pharmacology unit interchangeably with phase one unit or are they is there nuance between the two. No, I mean, that's I'm using those interchangeably. I think that I think one really should think about. I would say that not every clinic is a clinical pharmacology unit. And, and the reason I emphasize clinical pharmacology unit is is having that capability to do clinical pharmacology. So the ability to really have that emphasis on safety surveillance and sampling of pharmacokinetics. Right. So having the ability to do that multiple time point sampling those precious samples that have very specific handling. requirements that will ultimately undergo bioanalysis to have the pharmacokinetics of the drug delineated. So that's very, very critical to the mission and not every clinic can really do that. So it's quite a specialized function. I see. So going back to the, you know, trying to accelerate clinical development or, you know, drug development, have you seen things go much faster than they were 10 years ago, given like the complexity we've introduced to move things faster? It's a really interesting question and I would say it can go a bit of ways. I think, you know, it's a double-edged sword. I have seen, especially sometimes when small biotechs are trying to do too much in too short a period of time, it can sometimes backfire. So when you're trying to, you know, boil the ocean in one protocol, you sense that you have sort of one shot on goal and you're swinging for the fences as they say. That can often backfire because you're sort of going for unicorns, if you will. And sometimes, you know, that cohort that you're seeking of rare disease patients and your inclusion exclusion criteria can turn into such a slog and it can just add an inordinate amount of time to something that you thought was going to go really fast. And so sometimes it can actually turn into something that might have gone a lot faster with a different design. But yes, sometimes it's quite successful and sometimes we've seen tremendous acceleration and elimination of what we call white space. That is that sort of that time between phases or between studies where analysis was being done before the next phase of the study was initiated. And I think a great case in point was at the beginning of the COVID pandemic, we had the opportunity. And we've published this. We had the opportunity to put into human phase one trials a COVID antiviral, an oral COVID antiviral treatment that had never been in humans before. It had been in preclinical testing for other indications. It had been tested as an anti-influenza drug. It had been tested against a number of other viruses. And so when the pandemic hit very quickly, we were collaborating with with this biotech too. As as experiments were being done in real time, the preclinical experiments delineating the compounds activity, very potent activity, again SARS-CoV-2, sort of writing the dossier in real time to file the regulatory documents necessary to do the human testing. And we did it in the UK in our leads clinic. There was extraordinary collaboration with the MHRA, the UK regulatory authority. And that was just lightning fast. And it was just an extraordinary collaboration that just cannot say enough about. It was a sort of interrupt, but is the collaboration between lab pork and M-M-H-R-A, or are you talking about collaboration with FDN and M-H-R-A? So it was actually lab core, the sponsor, and then and the M-H-R-A. And then later, there was also tremendous collaboration with FDA, because that was a plan B in case we had an outbreak within our leads clinic. You know, we had plans to do the study in our US sites as well as a backup plan. And so the FDA was also very receptive and collaborative, but we were able to get the study up and running in our leads site, and we completed it in the leads site without having to actually execute it in the US. All aspects of this study were done at an unprecedented pace at the lead site. So we had dose escalations scheduled with just literally no white space. It was done in a safe way, but with just no no redundancy. You know, there was no waiting. It was really just done with no fat on it, so to speak. So what would have normally taken about a year, so we did, I believe it was eight, single ascending dose cohorts, seven, multiple ascending dose cohorts, and two food effect cohorts, that would have normally taken just about one year under normal circumstances with normal turnaround times of getting the bioanalysis samples done and the pharmacokinetic analysis done, and all the normal processes of recruitment and all the volunteer visits and the clinics, etc. And that was all done in 16 weeks. So I think that really, it was an extraordinary circumstance, because the clinic was otherwise essentially shut down because of the pandemic. And so it allowed, it allowed us to focus all of our efforts on this extraordinarily important clinical trial. So I wouldn't say it's necessarily reproducible, but at least it sort of gives an idea of the theoretical limits, you know, of acceleration of clinical research. How fast can you make it go? So I think that was a very valuable lesson, and the results were pristine. I mean, the pharmacokinetic results, the results of the clinical trial are absolutely pristine, and the drug received, ultimately received emergency softrization in record time. So it was quite exciting. Yeah, that's great. So other specific elements of the collaboration that you think could be replicated in the future for, you know, with the sponsor and government agency, like you've found like these were solid elements that we should really learn from and then take the same approach the next time around. Yeah, I mean, I think there are some, you know, there were some really foundational collaborative points that I think should be a part of every project. I mean, I think we had, we had team sponsor and Sierra teams well-formed within a day, essentially, of kicking off the first conversations, and we had our medical team working with their medical team to design the protocol. We had the medical writers join those conversations very early on, so there was very little sort of, you know, nothing got lost in translations, so to speak. So it was a very efficient process of writing the protocol. The project management process was very efficient because those, those teams were joined at the hip from the very beginning. We had very, very effectively AISON with the regulatory authorities because the regulatory authorities were very receptive to real-time conversation. Now, you know, that's difficult to replicate in the normal order of business. It was an exceptional circumstance. I wish that that could be replicated because it was extraordinarily effective to the degree to which regulatory authorities can be receptive to real-time conversations and guidance and be receptive to rolling submission of regulatory documents. That was crucial in accelerating that trial. Yeah, that's great. Going back to some of the fundamental things you mentioned about like just PK, pharmaconetics and pharmacodynamics, can you for those that are not familiar with those definitions? Could you explain that for them? What what they mean? Sure. So pharmacokinetics essentially tracing out the drug levels in a relevant body compartment over time. So in the most usual circumstance and the simplest circumstance, let's think about drug levels in plasma over time. So think about a pill that's swallowed and gets absorbed over a certain period of time from the small intestine. It achieves a certain plasma level over time. It achieves a maximum level. That's the T max is the time that the maximum level is achieved and then there is a decay over time. The time at which half of the maximum concentration is present would be the T 1/2, the half-life of elimination. We can characterize the roots of elimination, etc. So there's a whole characterization of the amounts of drug in the plasma, various amounts of time allows one to characterize the likely roots of elimination according to what that curve looks like. It's a very critical part of phase one clinical testing to characterize what the body is doing to the drug. It allows us also to look further looking at metabolites that may be present in the plasma. What is the fate of those metabolites? Very important stuff to characterize at the beginning phases of drug development. Pharmaco-dynamics looks more at what the drug is doing to the body rather than what the body is doing to the drug. Pharmaco-dynamics, we can think about biomarkers. The drug is ingested, it's achieving certain levels. If it's achieving what might be therapeutic levels, well, it may be interacting with its target receptor, which might be having some biological effect. If it's intended to, if it's intended to dilate blood vessels and anti-hypertensive drug, then a pharmaco-dynamic effect might be very easy to measure. It might be just measuring somebody's blood pressure. That would be a pharmaco-dynamic effect. If it's a more circuitous relationship with the biological effect, one might have to measure a chemical in the blood, a biomarker looking for some measure of biological activity that is an indirect measure of that drug's activity action on its receptor. That makes sense. The other things you mentioned about the couple of key elements with safety surveillance and in a sampling of the PK with being done multiple times. You said there were some specific handling requirements. Could you explain what those specific requirements are in terms of sample handling? They generally tend to be maybe. They vary. The method will differ depending on the specific compound. Not infrequently, it might involve refrigerated centrifugation. It's not necessarily something very simple. It could be refrigerated centrifugation and separation of the plasma and then immediate freezing of that plasma and shipping under frozen conditions. You have to ensure that the samples stay frozen. The conditions are going to, there's no blanket for all PK samples. It really depends on the compound. We need to ensure that for every protocol that we do that we're looking at the specifics for each compound and ensuring that we're adhering to the specifics for that specific compound. Whether the centrifugation is refrigerator or not, what the temperature under which the storage has to be before it's shipped and the temperature has to be shipped at, etc. It's all variables. That makes sense. Great. Anything else on the handling requirements? Just to say that it's very specific in each case and that it's something that we talk about a lot in our clinic and this is again something that differentiates a clinic from a clinical pharmacology unit because in a clinic blood may be taken from a patient. It might be a glucose sample and if it's collected in the wrong type of tube or if the tube is labeled improperly, if there's some ambiguity, well, it's not that big a deal. It's an inconvenience, but we can draw another sample. If it's a PK sample, if it's a sample for pharmacokinetics that has to be drawn at a very precise time, let's say 30 seconds after drug administration, there's no latitude. It has to be drawn at 30 seconds. It has to be drawn in the correct tube. It has to be drawn in the correctly labeled tube. It has to be then centrifuged at the proper speed, at the proper temperature, etc. All those details that I just discussed. So it's not replaceable. There's no latitude. There's no wiggle room. It can't be repeated. It can't be replaced. That's something we talk about a lot. That is the whole purpose of the clinical trial is in large measure to sketch out that pharmacokinetics curve. It's absolutely essential. Precision is essential. That's part of why we talk about a clinical pharmacology in it rather than just a clinic. As it relates to safety surveillance, what makes safety surveillance challenging? What are some of the difficult aspects of safety surveillance in the early? A lot of times, it's pretty routine, but sometimes it's really scary. I mean, at the end of the day, we are testing experimental medicines in humans. Sometimes, although many preclinical experiments are done, and a lot of data are reviewed to say, yes, we think that it is reasonably safe to proceed with this experiment in humans occasionally, things go wrong that are unanticipated and unexpected. And we have to be prepared to deal with that. So we have our highly trained, highly skilled doctors and nurses on the floor. It's ready to deal with any emergency. And it is critical to be prepared for any emergency. We have crash carts. We have protocols for emergency transfer and emergency care during transfer that includes advanced life support. And we occasionally have to do that. Probably the most common emergency situation is an anaphylactic reaction. It's rare, but it happens. And that's reversible. We can treat that. And we do that occasionally. But occasionally, we see things that are more severe and more unanticipated than anaphylaxis. Some occasionally, we've seen seizures reported in the literature, of course, back in 2006 or 2007, maybe was the famous T. Genero incident that occurred at the Northwick Park Hospital in London at one of our competitors. That was a-- that received a lot of attention in the media. It was an experimental drug that was given almost simultaneously to several volunteers who almost died, all required intensive care for a long period of time. All suffered what's called cytokine storm. This was at Paroxyl, I think, if I remember correctly. Correct. Yes. It was a drug that really acted as superantigen and massively triggered T cells in the body and triggered cytokine storm, which had not been anticipated. It was quite dramatic. And there was an inquiry, and a lot of lessons learned. I think there are a lot of positive things as a result of that tragedy that were enacted, where for one thing, it's unheard of now to simultaneously dose a whole cohort of subjects with an agonist experimental medicine that's never been in humans before. You would stagger dosing. You would do a first cohort just involved in one placebo and one drug recipient. So a lot of changes enacted in response to that incident. So it can be safety is always the first priority in phase one research. Hi, friends. Thank you for listening to the Clinical Child Podcast. And here is a brief message from our sponsor, Kalex. Kalex is a trusted name in medical imaging, having delivered imaging services to meet the needs of global bio pharmaceutical sponsors and clinical research organizations for over 25 years. Kalex's experience includes over 2,600 clinical trials and 270 FDA-supported approvals and spans multiple therapeutic areas with significant concentration in oncology and CNS-related drug development across all phases, geographic areas, and degrees of complexity. The depth and the diversity of expertise that Kalex brings to the table is unmatched. In fact, some of the industry's most recognized subject matter experts and experienced scientists are part of Kalex's medical imaging team who bring therapeutic modality and image analysis expertise to every clinical trial they support. Whether you are in early phase development, looking to partner, planning, to take your compound through regulatory approval, or even seeking breakthrough therapy designation. Lean in on Kalex's experience and benefit from a tailored core imaging strategy designed to help you meet your development goals. To learn more about how Kalex can help you with your medical imaging needs, visit kalex.ai. It's c-a-l-y-x.ai. Or contact your Kalex solution specialist today. Now back to our show. [MUSIC PLAYING] So since our topic is complexity with early phase trials, I think we touched on a few things so far. But are there any specific aspects of early phase clinical research or clinical trial conduct that tends to be more complex these days than other items? It's really interesting. The whole of it is quite fascinating to me. I think that probably oncology is out in the lead in terms of complexity, in terms of therapeutic modalities. We're really talking about cell and gene therapy, chimeric, antigen receptor, T cell therapies. I think oncology is probably more advanced than any other field in terms of engineering, combining engineering with the genome and applying it as a therapeutic modality. Those are certainly some of the most complex things imaginable. But it's certainly a case where we see complex therapeutic modalities. We see small interfering RNA in a number of different therapeutic areas. So it's really not limited to oncology-binding stretch. When we see super interesting antibody and antibody-like modalities, not only in inflammation, but in other areas as well. Phybrosis in cardiac disease. I guess I'm old enough now that I have an appreciation of history. When I look back, I sometimes look back at the very first PDR. PDR when I was in medical training was a very popular tool. That's so much anymore, I don't think. It got too big. How do you spell that? The PDR, it's just the abbreviation. I don't even remember what it stood for. But the PDR was sort of the compendium of every prescription drug available. Physicians' best reference. That's it. Thank you. So the PDR, I think the very first PDR was published in 1947-ish. I have a copy of it in my office. It's quite a slim volume. And if you look at it, it's absolutely-- it's kind of appalling. I mean, you look at the ingredients of things that were prescribed. And they were extracts from lymph glands of animals. And whatnot. I mean, it's quite barbaric. And you really don't have to go back that far. If you look at a PDR from when I was in medical training sub 30 years ago, it's the same thing. And if you think about it, the science fiction that we're working with today in 30 years will probably seem barbaric. So I'm just quite fascinating the half-life of medical information, the half-life of therapeutics and the advances that are being made is quite breathtaking. It really is. And I have an autoimmune arthritis. And if I had been born 25 years earlier, I'd be facing a lifetime of steroid therapy, which is just absolutely horrible. And here I am on an interleukin 17 inhibitor, which is just absolutely mind-boggling. And we're just scratching this. surface. I mean, I L-17 is still a blunt instrument. And then you think about all of the scientific advances that came together to enable a COVID vaccine to be available within one year of the publication of the genome of that virus, which in turn was identified within three weeks of the identification of the clinical syndrome. That's absolutely mind bending. So it makes me quite optimistic. And yeah, it's if we get out of our own way, it's quite remarkable we can do. So you're saying basically there's been more specialized treatments and maybe more like we as a society I've been filling a lot of gaps in in our diseases with with therapies, which is kind of what's making it more complex and as we're niching down on specific problems that we face. Yeah, I think it is this, it's the science, it's the basic science that is revealing, you know, as we understand more and more at a pinpoint granular level, the pathophysiology of disease, that in turn reveals how to target, how to make a disease, how to create a therapeutic strategy, how to drug the disease, yeah. And that's what's creating the progress. It is the, you know, and if you think about the tools that we have available to probe biologic processes and understand diseases at the molecular level, yeah, yeah, that's what's really driving it. And that's driving complexity, you think, or is that part of the equation? It is, it is. I think that comes, it's part and parcel. I mean, I think that, you know, they say the low hanging fruit is gone, right? True. I mean, biology is complex. And we do have the ability to probe deeper and deeper. The answers are rarely simple. I mean, in some ways biology is, in some ways it's simple, but in terms of intervening in a disease process, it's rarely simple, right? And at a molecular level, you know, the firepower that we're applying to understand, you know, if you think about the drugs that are being used to correct the molecular misfolding that occurs in the cystic fibrosis channels, that's not simple. You know, and the technology that has been applied to understand that molecular misfolding and then designing drugs to sort of, you know, geometrically support, create that three-dimensional scaffolding to fix the misfolded protein. You know, that's tremendously complex. But you know, that's exactly what it is. That's what's happened. Earlier we were talking about bioanalysis and I was going to ask you, what is that entail? Ah, so the technology for bioanalysis and I am by no means an expert, it's really cool technology, but it is liquid chromatography mass spectroscopy based. And so the equipment is pretty sophisticated, but is essentially at its core, it's really the mass spectroscopy that identifies the molecular components of the drug that sort of identifies that the unique structures of the drug, you know, that's what allows you to quantify them. Are there medical imaging? Is there medical imaging happening in phase one studies? Yes, absolutely. So, and this is really where, especially when we talk about some of the studies in patient populations, so if we think about studies, one of the very hot areas in pipelines is neurodegeneration. And so, MRIs in, you know, doing studies in patients with early Alzheimer's or Parkinson's or ALS. So, MRIs, we've seen, we've done phase one studies with pet scanning. So, imaging is not uncommon. Interesting, got it. So, these units have imaging centers that are part of, like you have equipment at your unit to be able to do like pet scans or? No, usually so, no. So, we would collaborate with a hospital nearby and so, we'll provide transportation and send our volunteers over to the hospital, have the imaging done, they come back to our unit, or sometimes if the study, so that would be in the normal healthy volunteer. If the study is actually being done in patients, that's where we would be collaborating with a university hospital that would have the capability of recruiting the patient populations and doing the imaging, you know, on site in their hospital. So, you know, all kinds of different permutations depending on the population being studied. I see. So, I want to maybe shift gears a little bit and maybe talk about, like if you're advising a sponsor on a phase, early phase study, you know, the brand needed this whole space, they've never conducted a phase one trial, I have very limited experience. I want to maybe touch on like maybe three key points in my opinion, but there could be more. Like, how would you advise them to think about their study design, including like endpoint definitions? Maybe let's start there and then I have a couple more follow-ups to that. So, it really depends on the molecule and the potential indication. I would say that overall, my general advice would be to not overcomplicate it. I am, as I was alluding to before, I was saying that I've seen instances where some companies getting over their head and try to bite off more than they can chew and it backfires. I'm kind of desperate. I'm on a crusade to prove where that breaking point is. It's really hard to prove where that breaking point is, where you actually defeat the whole purpose that you set out in terms of becoming more efficient, where you actually make things worse. But, I'm actually a fan of the more limited hybrid approach. I do like combined protocols. I do like a combined single-assigning dose, multiple-assigning dose, and food effects study. I think that can be combined in an efficient good way. You get a lot of good important information out of that combination. But, I think throwing in more cohorts beyond that depends. Yeah. What other cohorts are folks adding to this? Well, so, you know, the, what I would call the the Supreme Pizza where they throw everything in would also include the effect of age, gender, Asian ethnobridging, drug-drug interaction, and cohort in patients. Oh, there'll be separate cohorts for that. You're saying? Yeah. All of those separate cohorts. And they might throw in a intensive QT monitoring as well. So a QT monitoring? What is that? Right. So that's an intensive electric cardiographic monitoring, which is for, you know, So, you know, that gets to be, I tend to recommend against that. It's just to me that gets to be beyond the breaking point, even though I can't prove it to you. Yeah. So, is, okay, I understand. Why couldn't they be able to do subgroup analysis on those, like, specific items, like age, for example? Like, why would you need to have a separate cohort for that? I'm trying to wrap my head around that. Yeah. Well, so, you know, so phase one cohorts are relatively small, right? Yes, I see. Normally, you know, you're talking about, you know, eight in a cohort, six-get-active drug, two-get-perceive, so, you know, you can't really do a lot of subanalyses. I mean, you don't, you know, always need to do a cohort that specifically looks at effective age. You might have a reason to do it, but it's just not something I would pack into the initial protocol. Yeah. I must have had a really good reason to do it. Do that. Yeah. I think it's coming from a place of fear, maybe, like, you know, okay, maybe we fail at some cohorts, but then we really find some gold in the other cohorts. Do you think that's part of it? It's hard to say. I mean, I really do think that some of is just trying to be overly, just trying to be overly inclusive and trying to get a whole bunch of data, usually for the purpose of presentations for investors. Saving money. Yeah, and I'm just much more a fan, and I was at a small farm company. I mean, I know I understand the pressure. I'm just more of a fan of the fundamentals. I think, you know, getting, doing a very careful delineation of the farm of the fundamental farmico-canetics with the single-a-sending dose, multiple-a-sending dose, and food effect. I mean, a lot of this depends on the preclinical data. You need to be driven by the preclinical data, but getting those first fundamentals of the farmico-canetics are going to really pay it the way, and you need to get that first, you know, and then figure out what you need to go do next. And, you know, rather than trying to get the whole Mississippi River in a Dixie Cup, you know, go back to them well after you got the fundamentals. Yeah, I love your analogies here with the supreme pizza and the Mississippi, the Mississippi River in a Dixie Cup. All right, well, that sounds great. Okay. I love it. So, you know, I have so many questions, but we'll first, before I kind of get into my follow-up questions around that. Maybe we can talk about, so that's the, we talked about the study design. Anything about endpoints election you want to mention or definition, like how to add on, it's very therapeutic specific, but any general guidance on that. Yeah, so endpoints to Phase 1, you know, primary endpoints are going to be the pharmacokinetics and safety. I mean, that's it. Right. So, secondary endpoints may be exploratory, you may have some biomarker exploratory endpoints, but generally speaking, you know, you have very limited power. I mean, you know, these are small cohorts. You're really the purposes to delineate the pharmacokinetics and establish safety and tolerability. That's pretty much it. So, not a whole lot of controversy around endpoints. You're looking for PK and you're looking for safety. And then you can, you know, secondary endpoints absolutely fine to throw in some exploratory biomarkers understood. So, the next thing I want to talk about is site selection, you know, so how, what considerations should the sponsor pay attention to when it comes to site selections for, you know, Phase 1 units? Yeah, yeah, that's a big one. I mean, there are lots of different flavors, right? And I have very strong feelings about this. I do believe that it's a huge responsibility to conduct Phase 1 clinical trials. We're conducting experiments in humans. And I think it's extraordinarily important to have highly professional trained staff that understand not just ICHGCP, not just good clinical practices, but have a deeper understanding of medical ethics that have understanding of context. The staff that have heard of the TGNRO incident that understand the processes that are in place that should prevent another TGNRO from happening. A staff that are, you know, really well-trained and well drilled in advanced life support. A facility that is fit for purpose, right? I think that a facility that has, you know, a central nursing station with monitoring that does not have bunk beds, for example, is fit for purpose for Phase 1 human clinical trials. So, I think you can tell a lot about a clinical pharmacology unit by visiting it and walking around. So, you mentioned about the staff training and the medical ethics and kind of knowing beyond the, you know, kind of going beyond the GCP part of the equation, right? What other strong opinions do you have about tight selection? I think I want to know those, yeah. Yeah, I mean, also, I think location is also important. I think it should be in close proximity to a hospital with an emergency department and an intensive care unit should that become necessary and that there is a protocol for transfer, you know, that there's a line of communication between the clinical pharmacology unit and the hospital and that if that is necessary, that it's a smooth process. So, that's also important. Yeah, no, I think that makes sense. Anything else? I would also look carefully at some of the practices, some of the SOPs in the unit. For example, the dosing SOP, right? Uh-huh. Such a critical process and how sound is it? In other words, our dosing SOP is highly redundant. It requires the dose to be checked and double checked independently. Right. There's no situation where a dose can just be directly given to a volunteer. It has to be checked and double checked. I think that's important in a phase one clinical trial. Yeah. We also employ failure modes and effects analysis, so that the protocols that we do, we subject them to failure modes and effects analysis. So, we have our cross-functional study team do failure modes and effects analysis, so that the team asks, you know, they read the protocol and they focus in on what is potentially ambiguous in this protocol. How, what might go wrong? Reading this protocol, what might go wrong? How are we going to prevent it from going wrong? Is there a simulation? Is there a dry run that we might do? Let's fix it before it even happens. Right. Right. So, and the third thing I want to talk about is patient recruitment, you know, as it relates, you know, from the sponsor perspective, like, what kind of things you would tell them to set realistic expectations about how patient recruitment works in these type of studies? Sure. So, you know, phase one is a little different. So, we are generally recruiting normal healthy volunteers. And we are set up very specifically to do that. So we have we have call centers. We do advertising, multimedia, social media. We are highly specialized in reaching out to normal healthy volunteers. In a specific study, it might get quite specialized. Sometimes we're looking for post-menopausal females. Sometimes we're looking for only males of a certain age. So the particular advertising and reach out may be highly specific. But we're looking almost always for normal healthy volunteers. And we're looking to bring them in, not one at a time. We're looking to bring them in. Our sort of golden metric is to bring in a full cohort. So if an average cohort is eight people, you know, we want to bring in 10 to have two extra in case any of them fail the day of requirements so that we get all eight dose successfully. >> Understood. >> Yeah. So that's our promise. And our goal internally is to have about 94% re-cruitment of full cohorts on the first try. That's exceptional. We did achieve that before the pandemic. The pandemic has made it extraordinarily difficult to achieve those numbers. In fact, not able to get the full cohort at the same time, you mean? >> Yeah, very difficult. It's just, I think, you know, to be confined to the clinical pharmacology unit for various periods of time, right? Could be five days, could be ten days, whatever. And I think during the pandemic, the word confinement has become like a horrible dirty word. We've put a lot of effort into it. It's finally, the last two months have gotten much better. We're doing much better. We're not at our goal, but we're at a pretty good level. But for, you know, the better part of two years, it's been a real struggle. >> Understood. Yeah. >> Yeah. What I mean, I was reading this book by Jill Fisher, she's Dr. Jill Fisher. She's a, she is at UNC Chapel Hill, I believe. And she's done a lot of research on phase one studies and things like that. And one of the things she mentions in her book is that there's tends to be more people from underrepresented, like social economic backgrounds, African Americans that participated in phase one studies for, for, yeah, for money, basically. And, you know, I felt like that statement or that research basically contradicts what the FDA, Skydance document, you know, the FDA recently has the draft guidance or enrollment aid with underrepresented patients in clinical trials. And I feel like phase one studies are already swayed in the other direction. >> Yeah. >> What are your thoughts on that? >> No, you bring up a really great point. It's an important one. And, you know, we have the, I mean, everyone has a big focus now on diversity, equity, and inclusion in within our own organization in terms of the human capital, as well as the fact of the matter. The FDA guidance and the focus on diversity in clinical research, really the focus, if you think of the focus in phase two through four clinical trials and patients, that focus is absolutely appropriate. There is underrepresentation of minorities in the vast majority of those clinical trials. And that needs to be addressed, right? Now, in phase one, Dr. Fisher is right. There's overrepresentation of minorities because phase one trials do offer compensation. Now, that compensation is tightly regulated. The compensation is for inconvenience and time. But it is compensation. And, you know, people, you know, people, underprivileged people, disproportionately tend to take advantage of that. So, it's complicated. It's that there are a lot, I mean, it has the amount that is offered has to be approved by IRBs, institutional review boards, or ethics committees, right? So, it can't be just, you can't just make up the amount. It has to be, again, only for inconvenience and time. So, it can't be seen as an inducement, right? And it has to be, it has to pass ethical muster. But it is, it's a gray area, right? I mean, clearly the fact that underprivileged people are disproportionately represented in phase one trials, does tell you something. So, there is an issue there. I mean, on the one hand, it is, it's giving people an opportunity. And, you know, it's, I think, to some extent, that's a positive. But it's certainly an area of controversy that certainly deserves further discussion, and it's something that that we're sensitive to, that I think the more we shine light on it, and the more we discuss it, the better. Yeah, because I think her argument is actually, she feels like, anyways, I think from a participant standpoint, the participants in her book felt like the industry was taking advantage of them. Well, not all of them, but they were a subset of participants. And I think one of the things Dr. Fisher mentioned in the book, I think she kind of did like some math around how much these people actually end up making, you know, by doing phase one study, then it's not a whole lot of money. I think it was like 20 grand in the whole year. So, anyways, it was quite interesting. And I think, yeah, I feel like maybe the guidance document with the FDA could be more focused or specify around phase two, three, four studies, and not necessarily phase one studies, because that, you know, that's already there with phase one, if anything, we need to go into the other direction. Yeah. I think you're right. It is, I mean, when I visit our clinical farm cause units, I do make a point of walking through the wards and talking to our volunteers. And I would say there are very few of them that volunteer to that extent where they're, where they have a significant income from it. A lot of them do multiple studies a year, but it's a couple, you know, it's maybe two or three studies a year maybe. And they're grateful. You know, I have not encountered anybody who has been, who's told me that they feel taking advantage of now, maybe they just wouldn't tell me that's very possible, but yeah, it's certainly, it's certainly interesting to comment on, but in any case, I make point of talking and getting feedback from all our volunteers and, you know, the vast majority of them are very positive experience. That's great. That's great. Okay. I have a few more, a couple more questions hopefully and then we can wrap this up. These are shorter questions. What advice do you have for a patient who's trying to decide whether or not they should participate in a phase one clinical trial? A patient or a patient or a participant, yeah, participant, I mean, that's probably a better word. Well, and to your healthy volunteer. Yeah. Yeah. I would say a very important to read the informed consent. I mean, I think that anybody considering it, I would encourage them to do it. I think it's a lot of people feel good about-- a lot of-- when I ask people about why they're participating, yeah, some people say, yeah, it's good money. And they don't mind it. But a lot of people do say that they like the fact that it has the potential to help people. And a lot of people say, because a lot of people are young. And a lot of people have the insight to say that it might help people. It might help me. It might help my older me, which I think is pretty cool recognition. So I mean, I think it's important to recognize that everything has risk, right? Right. Mm-hmm. But if people are-- you read the informed consent and you feel reasonably comfortable, I think you have positive experience. Right. Absolutely. So you mentioned about single assending those, multiple assending those, and then the food effects. Could you just explain each of those terms in brief? Oh, sure. Yeah. So single assending those study means-- so you remember-- I talked about a cohort of eight people, six get the act of dose and two get the placebo. So single assing those just means that let's say the first dose is going to be 1 milligram. So that first cohort, that's 1 milligram. The next cohort gets a single dose of 2 milligrams. And then the next cohort gets a single dose of 4 milligrams, et cetera. This all pre-specified in the protocol according to the pre-colonical data and the modeling, the pharmacokinetic modeling. Now then the multiple assending doses, let's say the first multiple assending dose cohort is going to get 1/2 a milligram twice a day for five days. Right. And then the next one is going to be 1 milligram twice a day for five days. So that's single assending dose means one single dose that escalates with successive cohorts. The multiple assending is multiple doses over a certain number of days that escalates over successive cohorts. OK. Understood. And the food effect means some drug levels may get boosted when you co-administer with food. So especially fatty foods have a tendency to boost drug levels. And it can sometimes be significant. So that's a very just the simple experiment where you dose people with or without food. It's a specified meal. That makes sense. Great. Thank you for explaining those terms. And then just to wrap up our conversation, are there any favorite resources that you have about early phase clinical trials that you'd like to share with this group, the listeners of this episode? It's actually not that easy to find resources online about phase one clinical trials. Our LabCore website has some decent resources. The FDA has some reasonable resources. There are some good old-fashioned books. I hate to say I am that old, I think. Yeah, I love those. Yeah, it'd go for it. Yeah. But I guess I point people to this podcast. Yeah. Yeah, thank you. Yep. Absolutely. Yeah, I have a couple more interviews on phase one studies. One is from a gentleman who's at nucleus network. And I'll link it in the show notes for people to check out his interview. That will be published. Yeah, this has been fantastic conversation. And really appreciate you taking the time to kind of walk us to the different elements or aspects of these early phase studies. Was there anything else you wanted to share that we didn't get a chance to discuss? There's one thing I do want you to share about is your story about working with Dr. Fauci and your early research on HIV. I think it's pretty fascinating. I was telling my wife, I was like, I'm talking to this physician who discovered the HIV vaccine. I just kind of told her that. But I think that might be partly true or maybe fully true. I don't know. So maybe we can talk about that a little bit. Yeah. Right. Well, so right. I did my fellowship in infectious diseases at the National Institute of Allergy and Infectious Diseases. Back in the day, I actually started as a student, actually working on HIV before we knew what it was. And then later ended up doing my fellowship at NIAID in Tony Fauci's lab and spent a decade there at the height of the HIV pandemic. And yeah, that was quite an experience. And of course, Tony's been in the news a lot during the COVID pandemic. And actually, well, he didn't discovered the COVID vaccine. But one of the fellows who was-- I guess a year ahead of me was Drew Weissman in Tony's lab and Drew when Drew went to the University of Pennsylvania, it was partly Drew's work with-- and I can never pronounce her name right. I apologize, but she ended up at Bayon Tech. And it was their work together that was a seminal discovery that enabled the COVID vaccine to be made. It was their discovery that really allowed an RNA vaccine to be made. The whole problem-- one of the huge problems with RNA vaccines was that they were too immunogenic. And so the immune system would recognize and destroy what it perceived to be foreign genetic material. And so use-- it was the chemically modified RNA that was the discovery-- one of the key discoveries that enabled successful RNA vaccines to be made. So quite amazing. I think probably a Nobel Prize winning discovery in the making. But yeah, working with Tony Fauci for a decade was quite an amazing experience. It's learned a tremendous amount of immunology and have a lifetime of stories. That's great. That's great. This has been really phenomenal. So thank you for sharing all your learnings and experiences with folks on this show. I don't have anything else, Dr. Cohen. So we can call it a wrap here. Can all thank you very much, really enjoyed it, and really enjoy your podcast. Thank you. Hi, friends. I hope you enjoyed this episode on the Clinical Trial Podcast. Before we say goodbye, I want to share with you a quick story about our sponsor, Kaelix. When I joined the clinical research industry in 2005, my first job out of college was working as an imaging research assistant at perceptive informatics. Not too long ago, perceptive informatics rebranded itself as Kaelix. Almost two decades later, here I am with Kaelix as a sponsor for this show. I'm sharing this story with you because Kaelix has stood the test of time. The team of medical imaging experts has been front and center for over hundreds of clinical trial protocols with medical imaging endpoints. They've been through FDA audits and have experience working with dozens of clinical trial sponsors and CROs. In other words, they've been there done that. I hope you'll consider Kaelix as your imaging partner for your next clinical research. trial. To learn more, please visit calix.ai. It's spelled as C-A-L-Y-X dot AI, or contact your calix solutions specialist today. 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