Warner Huh, MD (Host): Hello everyone. This is Dr. Warner Huh again, the Chair of the Department of Obstetrics and Gynecology at the University of Alabama at Birmingham and like to welcome you to this monthly episode with Women's Health with Dr. Huh. Today, we're going to talk about Clinical Trials 101. And with me today is a true expert in our department, Dr. Rebecca Arend, who is an Associate Professor with tenure in the Division of Gynecologic Oncology and in the Department of OB GYN. She's also a Scientist in the O'Neill Comprehensive Cancer Center and holds actually two very key important roles in the Cancer Center, including she's the Co- Leader of the Experimental Therapeutics Program, and she's also the Medical Director of the Clinical Trials Office in the O'Neill Comprehensive Cancer Center.

The reason I raise these two positions is that they're very much central to clinical trial operations and execution as they relate to cancer in the O'Neill Comprehensive Cancer Center and UAB Medicine. So, Dr. Arend, welcome to the podcast this month.

Rebecca Arend, MD: Thank you so much, Dr. Huh, for having me. It's a great opportunity. I'm happy to be here.

Host: So you're like the ideal person to talk about clinical trials because, you really have dedicated your entire career to these and have contributed enormously, particularly on the cancer side, particularly in gynecologic oncology. But the reason I invited you today because I thought you'd be the perfect person just to talk about what clinical trials are and its importance to our listeners.

So maybe we'll just start there. Maybe you can explain what a clinical trial is and then talk about why they're so important to clinical medicine.

Rebecca Arend, MD: Yeah, thanks. I actually had this conversation with my family this weekend at the beach. My parents were asking me the same question and the kids and I said, you know, what I like to explain to people is the fact that almost every single medication that you take for any illness or any vaccine that you've gotten in your life to prevent an infection, the only reason it's available to you today is because of a clinical trial. That's how treatment gets approved. So all medication really originates from research and all research that's done in labs or rats or mice or whatever, and that's what we call sort of pre clinical research.

It at some point has to be safely done in people in order for it to get approved. And the agency that approves it is called the FDA, and that's the Federal Drug Agency. So any drug that you take, whether it's prescribed by a doctor or whether you buy it at Walgreens, it's FDA approved. And everything that's FDA approved was all done because it was part of a clinical trial.

Host: So, one of the things I think that a lot of our listeners, either as patients or being friends or family members to patients, is they hear about the different types of phase trials, like they'll hear a phase 1 trial, a phase 3 trial, but you and I both know that there's a phase 1, phase two, phase three, phase four and phase one and two have different categories.

We're not going to get into that. I think it's beyond the scope of this podcast, but can you just briefly take the listener through those steps of the different types of phases? And I think that actually might be helpful to put this into context for the subsequent questions that I have for you.

Rebecca Arend, MD: Yeah, sure. So sometimes we even refer to phase zero as, some of the preclinical models when it's done in mice or monkeys or rats or what have you. And then once, all the data that can be done before it goes into a human is accomplished, then it does need to be approved and looked at in humans.

And so that's usually called a phase one trial. And so the goal of the phase one trial is to figure out what dose is safe in a human. So it's not necessarily what does that drug do, how effective is it, but how much of that drug can the patient take. And then, sometimes that's actually done in healthy individuals, sometimes it's done in cancer patients, but then ultimately in order for the drug to get approved, it needs to go to a phase two and sometimes drugs actually get approved through a phase two, but most of them need to go to a phase three.

So the phase two portion is when you're looking for efficacy. So is the drug doing the thing that you want it to do? So, so in the example of cancer; is the drug actually decreasing the size of the tumor or is the drug actually prolonging the patient's survival? And we look at that in a small number of patients and that's usually what a phase two is.

And then before it gets approved, we sort of compare that to the standard of care. And when I say standard of care, that is what you would get if you just went to your oncologist. If I went to my oncologist with advanced ovarian cancer, I would get chemotherapy called CarboTaxol. But if I think that something in addition to CarboTaxol may actually be better for that patient, it goes to what's called a phase three.

And so one of the types of phase three trials that you'll sometimes hear us talk about is something called the gold standard, which is a randomized, control, double blind, placebo trial. I know that's a mouthful and you don't always have to say it, but I, like to break it down for people to think about.

So what is randomization? When you say randomized, what does that mean? And what that means, is the same thing that we teach our kids. If you flip a coin, 50 percent of the time you're going to get heads, 50 percent of the time you're going to get tails. And so that's what happens when you enter into a randomized trial.

It's like flipping a coin. So if that trial is one that we call open label, then you know which group you're going to go into, either A or B, and the patient knows, the doctor knows, everyone knows, but sometimes in order to make sure that there's no what we call bias, like I'm not, selecting patients to go on this or patients don't know they're getting the experimental drug, so they try and take it more precisely, what have you, then it can be what we call blinded.

And that's where you don't actually know if you're getting the additional experimental drug in addition to the standard of care. And then sometimes take that a step further, we say, okay, in order for you not to know, you have to be taking something. So whether it's a sugar pill or whether you're put saline in the IV, nobody knows who's getting what.

So that at the end of the trial, if the arm A that we think is going to be better is actually better, we can all confidently walk away and say, it is better. I didn't choose the patients that I wanted to go on arm A, arm A didn't even know they were getting the real thing. That truly is better. And that's what the phase three trial is.

And that's usually what we call the gold standard before it's FDA approved.

Host: So there's a lot to unpack there. So can you just, for our audience, explain why it's important to have a placebo? You did a great job explaining the importance of randomization, a patient gets drug A, drug B, the way I describe this to my patients is the best way is if you're doing a randomized trials, if you were blindly comparing Coke versus Pepsi, for the listeners, I'm not sponsored by either company, but that kind of gives you an idea of which one tastes better to you and then you basically release the results. But tell them why a placebo and I'll get into this later, why that's important.

Rebecca Arend, MD: So I think one of the things I like to say is important is for instance, if I was the doctor who really believed in this new drug that I was enrolling you in and I said, you're gonna get the drug and so therefore it's really important for you to take the drug on time. It's really important for you to come into your appointments because I know that you're getting the drug. You think it's going to be better than the standard of care. I think it's going to be better than the standard of care. Then you may actually be behaving differently. So what a placebo is, is you have no idea whether that extra thing that you're getting is real or not.

So that's, it sort of levels the playing field in a way so that the person who is getting the quote unquote fake drug or the saline or the sugar pill doesn't know it. So they're not at home being like, I'm not on the actual drug, so who cares? I'm not going to actually take it at nine o'clock at night, or I'm not going to come to the doctor next week because I'm not really getting the real thing.

So it's important to have a placebo for that reason, so that you make sure that at the end of the trial the data is real.

Host: You hit the nail on the head. And I think the other part of that is not just the patient right, but also the investigator. Yeah. And this issue of bias. And, by giving a patient or a subject placebo, it reduces the bias that one also has in terms of understanding whatever intervention, drug, etc. is. So, but you're right, just so our audience knows, I know you know the answer to this question, but the downside behind running a randomized controlled trial that's placebo controlled.

Rebecca Arend, MD: So the downside is that you may be getting the placebo. So at the end of the trial, you're like, doc, I went through all of that. And sometimes you may never know. You may never know that you got the placebo. So that's the downside. But what I always like to tell patients is that, you wouldn't be getting this extra thing, if you didn't enroll in the trial. So you'd just be getting the standard of care. So there's no even possibility of getting the next best agent that patients are going to get 10 years from now that may be the next cure for cancer.

I know that's a little aspirational, but, the only way for you to even get a chance of being part of a cutting edge therapeutic that's up and coming, is to enroll in the trial and at least have the possibility of getting it. But I can understand why, it'd be a bummer for somebody to feel like they put in the extra time and the work and then they were taking something that wasn't real.

Host: And then the other thing I think is also important to recognize is that they're extraordinarily expensive to run. I think the cost of running a randomized trial, obviously our audience may or may not know this, but it's exponentially more expensive. There are a lot more components, a lot more complicated. The blinding that we're talking about, the placebo, all that stuff costs so much more. So even though it's the gold standard, you pay a price for that gold standard.

Rebecca Arend, MD: Yeah. And to piggyback on that, that's why I was saying that actually some drugs are now being approved in a single arm phase two trial. Because they're so much better and everybody knows it that nobody's making us prove it. It's like, wow, that trial nailed it. It hit a home run and we don't even have to go compare it to something. So that's happening more and more. And we'll get to this later, but that's happening more and more in sort of this personalized medicine space that is becoming more of the standard of care.

Host: I'm glad you mentioned that because, with cost comes time and with time becomes slower discovery and slower discovery means slower approval, which means that takes more time to get the drug or therapy out to the patient. So it's nice to know that we as profession, as well as regulatory vis a vis the FDA, have streamlined these drug approvals, particularly while looking at safety, making sure that we're giving something that's safe, but also recognize that there's a clinical signal of benefit in getting those out to the public so that we can actually improve health.

So I think it's nice to know that. And perhaps that this traditional paradigm of using the randomized controlled trial may not in fact be necessary. It may be overkill.

Rebecca Arend, MD: Absolutely.

Host: So you brought up something that I'm just going to just dive right into. And I know you deal with this issue a lot. I deal with it every now and then too, is this placebo issue. Like I think I've had many patients during the course of my career who is like, well, is there a placebo part of this trial? And if I say yes, and there is, let's say, a 50 percent chance that you're going to get the placebo; there's obviously patients who would say, I'm just not going to go on it because I want to get the experimental drug. How do you reconcile that with patients? I mean, like, do you have a particular strategy that you tell patients? Yes, I recognize it's placebo control, but I think you need to go on this trial for this reason. I'm just kind of curious about how you approach that situation.

Rebecca Arend, MD: Yeah. So the way I like to say that is that, if you do in fact receive the placebo, as part of the clinical trial and that leads to an approval, then you will actually be able to get that drug. So you're saying to yourself, okay, I'm willing to be part of this process right now.

And that's part of why we have what's called the IRB, the Institutional Review Board, we have ethics committees that are taking a really close look at these things to make sure that somebody who is getting the placebo, if for some reason it's discovered, and this has happened before, that it's discovered sooner than expected that that drug was so much better, that everybody was unblinded and you were able to what's called crossover and actually receive the drug. And if you weren't willing to participate, then not only would you not be able to receive the drug, but also other patients, especially for cancer patients to think, how am I helping? Even if this doesn't help me, what if my daughter, got the same type of cancer.

What if it was a cure that she benefited from? Even if I didn't benefit from it, knowing that I was a part of that discovery, I think really does help patients.

Host: Yeah. I really like that actually. And I want to go back to something that you said in the very beginning of this podcast that deserves to be emphasized, which is almost everything that we take as a drug in this country, went through a phased process of study. And so when patients take a certain drug and they benefit from it, let's take something as, commonplace as Tylenol; those are subject to clinical trials to understand the risks, the benefits, and this is how we advance medicine. I mean, this is how we get better therapies out to the public and improve health and lifespan and healthspan, et cetera.

One of the things I know that you're passionate about, I'm very passionate about this, but I think it's important for our audience to hear this because I'm pretty sure that many people don't think about it this way is, why would a patient go on a clinical trial? I know you mentioned briefly in the cancer world, and you and I both work in this setting where that gives patients access to novel therapies for truly a life threatening illness, but are there other things that you think are relevant for the listeners to appreciate about why it's arguably better to go on a clinical trial than standard of care.

Rebecca Arend, MD: Yeah.

Host: I thought you may want to comment on that.

Rebecca Arend, MD: Yeah. I'm glad you asked me that question because, and again, I'm biased towards cancer. But in particular, for cancer patients, I have many patients and I know you do too, that are still alive today, that have been on multiple clinical trials because there was a time where we said, okay, there is a standard of care option. We can always go back to that, but let's think outside of the box. This may actually be better. And then we've put them on a trial and we would have expected them to only be progression free is what we call it, or survive six months.

And here they are five years later, walking into our clinic, and people have actually looked at that and said, patients in the long run with cancer do better when at some point they have participated in a clinical trial.

Host: And I think that's the point that I really wanted to stress to this group is just that. I think oftentimes our patients don't realize that they're actually observed more closely on the clinical trial than they are under standard of care. And I can't tell you how many times I've had patients who come off of a clinical trial mainly for good reasons.

And they want to go back to that original model of care because they felt that there was always someone looking over their shoulders to make sure that they're doing okay. But in reality, I think people don't realize that, you're being observed much more closely. And I think patients, particularly our cancer patients, are shocked by that, actually.

Rebecca Arend, MD: And the support that they get, and I've heard people say this, you know, just like you said, when they come off the trial, they're like, what happened to, the weekly phone calls or, making sure that I had an hour long conversation with three people or the extra scans or what have you, that you are really being taken care of to another standard, because you're being watched so closely.

Host: So you mentioned something very briefly. And I want to go ahead and leapfrog to this comment that you made about precision medicine and talk a little bit about what you mean by precision medicine. I think some of our listeners may not know that terminology. So kind of at a high level talk about that, but then more importantly, I know this of you, but why do you think that that is so central and important to the future of how we care for patients, cancer and otherwise?

Rebecca Arend, MD: If you think about the discoveries that we've made based on, and I used to be a biology teacher, so DNA becomes RNA becomes proteins, and that's why cells divide and become abnormal. And the more we can understand in your particular tumor, and I'm going to talk about cancer specifically, but it doesn't just pertain to cancer, if we can understand, if we're talking about cancer, what DNA change or what RNA change or what protein that's expressed in your cancer that we may have a targeted therapy for, that's not going to work in everybody.

But we know it works in yours because your cancer has, let's say a protein, let's say it's holding a sign up that says, come eat me. And we just discover a drug that can only see cells with that sign. And believe it or not, we're actually having trials that are exactly that. But in other types of scenarios, not just cancer, looking at the genomics of a patient or how they may metabolize the drug.

So, understanding the differences in the human DNA and the differences in the people who walk into your clinic, whether it's based on your metabolism, your weight, your race, how old you are, and taking all of these things into account and making sure that we are not just doing one size fits all, and that is really where the field is going and it's pretty phenomenal to watch because as you know, when I started this journey as your fellow, years ago, we gave ovarian cancer patients the exact same thing. Every single patient got the same thing. That is not the case anymore. And when you look at, say, something like immunotherapy, which, we used to think was the end all be all for cancer and GYN cancer, which we treat, it's not the end all be all for everybody.

But now we've started to figure out who it works in and who we can spare the toxicity. So we don't want to give it to patients if it's not going to benefit. And the field has really come a long way in that arena.

Host: Yeah, I mean, this is the future. It absolutely is. And we're not just seeing it in the cancer side. I mean, we're seeing it even in women's health. We're seeing it in cardiology. We're seeing it in rheumatology, pulmonology. We're seeing it in all the fields. And I think the world just is going to look completely different in the next five to ten years is we're kind of living that change right now.

And it's scientific discovery is moving at such a fast pace that it's almost, I almost struggle keeping up with it, because it's changed so much. So one last question to you, and I think this is really an important question to ask before we close out, which is, why would patients or perhaps our listeners, regardless of the clinical discipline, so not just cancer or women's health, want to consider receiving clinical care at an institution that offers clinical trials? I know that you have thoughts on this, but I just thought we should share that to the broader public. The why.

Rebecca Arend, MD: The why. And I think that's a really important question because in my opinion, clinical trials really should be the standard of care. And even if the patient chooses not to go on the trial or the patient is not eligible for one reason or another, I mean, I've always been a huge advocate of equal access to everyone.

Everybody should have the same menu in front of them to choose from. And if one of those things is a clinical trial, then if that was my daughter, if that was my mother, I would say go somewhere where that's an option. Not only because maybe you could get on the clinical trial, but also that signifies that that's a place where the cutting edge research is being done.

That's a place where they are, like you said, it's hard to keep up. But I know that if I'm somewhere where the clinical trials are happening, then they are at the forefront. So when that drug does get approved, that's a place they have experience with that drug. They may have even invented the drug.

And I think that that's really important for patients to understand is that, going to a place that at least offers that, in my opinion, really should be the standard of care.

Host: I could not agree more with that. And I think that's really important and something that when I went into clinical medicine, I don't think I really appreciated that. And as I've gotten more mature and experienced, I think that should be a huge consideration for patients, because I think it also speaks to the level of expertise, resources, but also, the depth of experience that a group has if they're going to take on clinical trials, right, because they're looking at the broader picture of care.

They're not just looking at what's available by toolbox today. Well, this is amazing, Dr. Arend. I mean, this is really one of the most thorough primers on clinical trials that I've heard in a long time. Like I said, I knew that you'd be a perfect person to talk about this, and so again, thank you for participating in this.

And as always, please rate this podcast, and we welcome any comments, particularly on topics that you all are interested in, and please keep on sending the feedback, because our podcast agenda has changed based on the feedback that we received related to this. And then for more information on clinical trials within the O'Neill Comprehensive Cancer Center, the Department of OB GYN, otherwise, throughout UAB Medicine, and all clinical services that UAB provides, please check out uabmedicine.org. And until next time, thank you, have a great day, hope you all are enjoying your summer. Take care. Peace out.