Understanding Clinical Trials

BrightFocus Foundation
“Understanding Clinical Trials”
Transcript of Teleconference with Chris Brady, M.D.
October 28, 2015
1:00 — 2:00 p.m. EDT

Please note: This chat may have been edited for clarity and brevity.

GUY EAKIN: Hello, everyone, welcome to our monthly BrightFocus Chat, presented by the BrightFocus Foundation (BFF). My name is Guy Eakin; I’m the Vice President for Scientific Affairs here at BrightFocus, and I’d like to welcome our speaker today, Dr. Christopher Brady. He’s an ophthalmologist at Johns Hopkin’s Medical Institute, and he specializes in retinal diseases such as macular degeneration. His research arm apart from his clinical practice is looking at new ways of screening retinal diseases through technologies that may be both everyday technologies, like smartphones, as well as cutting edge technologies that we haven’t heard of yet. Today, the subject of the call is clinical trials. So, many people have heard of clinical trials and the promise of those cutting-edge treatments offered through these studies, but what are they, and how do they work, and how do we find more information about those new studies? So, Dr. Brady, welcome to the chat. As you know, we host these calls monthly and often talk about treatments that remain under study and clinical trials, and we use this word rather loosely, I have to admit, sometimes for things that cover a really wide variety of topics. So in your practice, if a patient comes to you talking about a clinical trial, in broad terms, what might they be talking about when you hear those terms?

CHRIS BRADY: Well thanks Guy, it’s certainly a pleasure to be on the call with you today. So, I think for me, if I hear the word clinical trial, that means to me that there’s some sort of research question, some sort of piece of knowledge that we may not fully understand, and we feel that it’s necessary to do some kind of controlled experiment under more controlled conditions than a typical doctor-patient encounter to try to learn something new. And that is a pretty broad definition—to hammer it down, most often we mean a new drug: is this new drug safe and effective for a condition?

GUY EAKIN: When you talk, you say sometimes we mean a new drug. Could you elaborate on other places where we might have a clinical trial—what falls outside that idea of sometimes we are talking about a clinical trial for a new drug, that is?

CHRIS BRADY: Absolutely. To sort of draw a circle around what is a clinical trial and what’s not a clinical trial, you know—there I just was focusing what’s a trial. What makes it clinical is the fact that we’re testing an intervention in human beings. So, we are using people, and we are comparing something to something else; that doesn’t at all—as you point out—have to be a new medication. It could be a new type of surgery, it could be a new type of physical therapy, it could be a behavior intervention, it could be a diet—anything that could be an intervention could be studied with a clinical trial.

GUY EAKIN: I think sometimes we hear—if we read in the technical literature, we will see people talking about a clinical trial, which is these studies where we are looking at an intervention. Interventions come in a lot of flavors: you mentioned surgeries or drugs or physical therapy. Sometimes we will see the word “clinical study,” which also requires people to be involved in that, but maybe outside of that. Could you give an idea of the breadth of the research that might be occurring in your department that requires human subjects—or human participants, rather, I think that’s a better term—to participate in that research enterprise?

CHRIS BRADY: Absolutely. I think that, you know, the broader term of “clinical research” includes a lot of things that would not necessarily fall under a traditional clinical trial. Again, for me, I think formally clinical trial means taking an individual and giving them something and seeing what happens. A lot of what we do in our department may be clinical research, but it may not be a true trial, it may not be a—you know, to think about the word—it may not be trying something and seeing if it works. It may be something where we are taking a new type of photograph of the eye to see if that helps us understand a disease better, maybe a new type of retinal scan will give us better information about macular degeneration or another disease and help us understand that that test. Well, heck, maybe that test is better than the other test we’ve been using, and maybe we should switch to this new test. Other things maybe a retrospective trial and that would be—there wouldn’t necessarily have to be a new patient, someone who is deciding to participate in that trial, but it would still be clinical research. For example, I may decide I want to look at my practice and over the past 5 years or so: how did everybody do when they were given a particular treatment? Or all the people that I saw with macular degeneration, what determined how they may have fared? What were the features of their disease? And that is still clinical research, but it’s not something that a person could necessarily decide to participate in. Still using human information, but it’s not an active participatory thing.

GUY EAKIN: For people who might be considering whether or not they would like to participate in clinical research studies, and certainly we will spend most of our time today talking about those ideas of trials, but they may wonder whether they would be eligible to participate. Could you give us an idea about what eligibility looks like from the standpoint of the doctor who is recruiting into a trial and whether there is a role for people who might not even have the disease at all?

CHRIS BRADY: Of course. So, right off the bat, often times it can be hard to know if an individual may qualify to participate in the trial—if they meet what we would formally call the study population or the inclusion and exclusion criteria—and it takes the investigator or the staff of the investigating doctor to carefully review the patient what those criteria might be. For example, the most obvious inclusion criteria for a clinical trial about macular degeneration—and I’ll speak to your second question in a minute—might be that someone has macular degeneration. And that may sound obvious, but there are—some diseases can look just like macular degeneration, and so for a clinical trial there may be criteria where you have to have certain photography done, certain testing done, that may have to actually be interpreted by—not necessarily your study doctor, but it may be interpreted by a centralized laboratory. And the reason why I bring that up is, for people who do decide they might like to participate, that can be a common reason why that the screening visit can—there can be a delay between when that testing is done, when you sit down and try to figure out if you can participate, and when you can actually start the study. There may be other things, again, that you wouldn’t necessarily be able to know without sitting down and really going through the paperwork. For example, you may study a new medication that has a known—is known to have a particular side effect, and what we might want to do for safety purposes is try to only include patients who aren’t at elevated risk for that side effect. So, for example, let’s say that we knew the medication maybe can be harmful to the liver or the kidney, we might specifically want to make sure that someone with severe liver disease or severe kidney disease not participate in that study until we understand the medication better and we can understand what the risks for that individual might be.

GUY EAKIN: I think the other part of the question was around healthy volunteers—so, people who may or may not have the disease themselves, or it might be in an earlier stage. What would you say to those people who are potentially considering whether or not they might have an opportunity to help advance science by participating in a clinical trial?

CHRIS BRADY: Well, I think you phrased it quite well. First of all, I would say thank you, thank you for considering to spend your time and your effort and frankly your body to help people with these diseases potentially do better in the future. We may talk about, a little bit, in the coming up, the formal structure of different types of trials, and so there are opportunities for what we call healthy volunteers, or healthy subjects, to participate in earlier phases of clinical trials. This is when a drug company or an investigator has substance that they think might work for a certain disease; it’s been evaluated, perhaps, in the laboratory or maybe in mice or other animals and appears to be safe, but it’s never been tested in humans before. We try to be very careful and frankly use small numbers of individuals when we start a study like this because we don’t know side effects may occur so it’s truly for people who have that altruistic streak that want to sort of give something to the future of science or people with these diseases and frankly not get much in return in terms of treating or curing a disease. This is the easiest—sort of to understand in terms of, you know, you’re going in there basically as a volunteer to help out and you’re not expecting that you’re getting any physical benefit from this medication.

GUY EAKIN: You hit on something interesting in that discussion that is a little bit apart from where I was sending the question, but you talked about the burden of proof of what’s necessary to actually consider a drug for human clinical trials. Could you talk about that that workup? How does a drug go from being an idea in a scientist’s head to actually being exposed to human beings?

CHRIS BRADY: Absolutely. What you don’t want to do, is you don’t want to, in your garage or in your fancy laboratory, come up with something that on paper or in a computer simulation or theoretically should cure macular degeneration or some other disease and have no side effects and then put up an advertisement for a clinical trial. And there is no way you could really do that. You need to start building a very strong case of evidence that the medication has some sort of theoretical and some sort of scientific explanation for why it should work. You want to—in this day and age, it does involve computers. We can sort of learn things through pure simulations. There is also the opportunity to take advantage of pure laboratory science. What we call in vitro or truly test tube type of studies and then a little bit more advanced than—more complicated testing—medications in animals. So, we do have animals whose—all their organs can mimic human diseases. We would have what we could call a model for macular degeneration, and we can try these therapies against non-human animals and see both how safe the medication appears to be and how well it may work. And once you have reached all that, then you start putting together reams of paperwork supporting what you’ve done so far, and at that point you can start thinking about testing these types of treatments in humans. And, as they said, the first step is testing in very small numbers of people and seeing how people react.

GUY EAKIN: If I could interject you mentioned that—reams of papers, and I think we all have familiarity with putting together a lot of paperwork around medical issues. The Food and Drug Administration oversees the approval of new medications. I’m wondering if you could describe the relationship between that FDA—the Food and Drug Administration—and the trial sponsors. And so, that paperwork that you’re describing, what’s the nature of that relationship between those two entities?

CHRIS BRADY: Great question, and it’s personally to me a very interesting question because that relationship has changed over time, and it’s changed over time because of developments in medicine, developments in culture, developments in politics. And so I think it’s a really key point that—and I think we’ve gotten somewhere interesting in this conversation—because I think that many of my patients are interested in access to cutting-edge therapies or new treatments, and there is this whole world that’s behind all that, which is, why are these studies occurring in the first place? Why is this happening? And, ultimately, the point of these formal clinical trials is to take a new therapy and get it into the marketplace, get it so it doesn’t have to be in a clinical trial, so that your doctor can prescribe that medication for you and for anybody else. And so, the study’s sponsor or the drug company who has a new idea or has a medication it thinks might work for macular degeneration, they are really in constant communication with the Food and Drug Administration, because what they are doing is saying, “Listen, we have this medicine,” or, “We have this chemical compound,”—I mean, frankly, it’s probably not appropriate to call it a medicine at this stage—but, you know, “We have this chemical that we think will help with macular degeneration, here is our research so far, here’s what we are planning to do. We want to test it in humans, and then at the end of that we are going to submit our results to you, and if you think it’s appropriate, then we will put it on the market and it will be available for all patients.” And so each part of that trial is a constant communication between the company and the FDA.

GUY EAKIN: We know there is a real bottleneck, or a funneling, I should say, of—it takes about 10,000 drug candidates to look at to try to get to one FDA-approved drug. And we hear in the newspapers around a drug that might be entering a phase 1 or phase 2 or phase 3. Once you begin that conversation with the FDA and you begin scheduling out these series of trials, what do those phases mean and how do they relate to the progress of getting a new drug to market?

CHRIS BRADY: It’s a great question. And I think when just to back up for a second, when someone with macular degeneration hears about a new medicine and is interested in participating in clinical trial, at that point largely what we are talking about is what we would call a phase 3 clinical trial. And this is—phase 3 clinical trials are sort of by far the largest number of participants. These are the biggest studies, and these are the studies that I think most people would think of when they think about a clinical trial. That’s when you have a new medicine and you’re testing it to see if it works for certain disease and you’re going to compare them to someone else. Phase 1 studies, to go back, that’s what I was talking about when I said a healthy volunteer, a very small number of people, essentially to find out if it’s safe, if people have severe and unexpected side effects. Phase 2 studies, the easiest way to think about that is somewhere in between. Larger number of people starting to look to see if it might work, maybe you’re trying to figure out things like the exact dose, is it 100 milligrams or 200 milligrams—well, maybe you’re going to compare those two to see if there are side effect differences or differences in how well they work. Do you give the medicine once a day or twice a day, do you give it once a week, once a month? Hopefully with the background research that’s been done, investigators, the drug company, the FDA are going to have ideas about those things. Phase 2 is the opportunity to test those out. And, you know, it’s not a direct path if you say, “Oh, I’m going to do three phases of the study.” Well, you have to show that each phase works before moving to the next phase, and so if you’ve had a successful phase 2 study, that’s when you can start thinking about that larger trial, and the phase 3 results are the most important in terms of getting that FDA approval and for getting it into the market.

GUY EAKIN: For a patient who comes into you asking, “Are there clinical trials in my area?”—someone who might be interested in participating—where would they go to find out more information about what trials are available in their area?

CHRIS BRADY: I think your two best resources are going to be—number one, your retinal physician. So, for people with macular degeneration who have an ophthalmologist or a retinal specialist, the first point of contact—I think it makes a lot of sense—would be your own personal physician. They personally may not be participating in clinical studies, or they may be participating but maybe they don’t have any actively recruiting trials, but they are going to know their community. They are going to know, “Okay, you’re my patient, but if you’re interested in clinical research, I know Dr. Jones or Dr. Smith down the street, or at the university, they frequently are doing clinical trials, maybe we can see if they have anything going on.” That would be, I think, would be your first and best point of contact, because that doctor knows you, knows your disease, and may have some degree of lay of the land in terms of what’s going on in the immediate community. The other resource would be what we call clinical trial registries. These, if you have access to the Internet, or friends or family members that can do this research with you and for you, I think that’s how a lot of times people’s family members point out, “Oh, have you tried this, have you heard about that?” But clinicaltrials.gov is the website. It is supposed to be usable by scientists, doctors, patients, and, frankly, the general public and policy makers as well. I don’t know how successful they are at that goal. It may still be somewhat technical, but I think they try to make it available and accessible to all people. The value of clinicatrials.gov and other registries is that every study that’s going on, every clinical trial this day and age, should be on that registry. And they have flags on the website to tell you what stage of the research it’s in—in other words, is this still actively recruiting—and it can give you a little bit of background. Many of them will have all of the—what I mentioned before—the study criteria, the inclusion or exclusion criteria, so you can get a sense on there if you might qualify. For example, they may have an age limitation and you may not qualify for that study, even though it’s going on in your area, because you’re outside of the age range that they are looking for.

GUY EAKIN: Within clinicaltrials.gov, or if you have a referral from your retinal specialist, and you go and talk to the study coordinator for one of these trials, what does that conversation look like, and what type of information will you receive, and what expectations should you have going into that conversation?

CHRIS BRADY: Great question, and I think that thinking about that in advance of meeting with someone is a great idea, because nobody wants you to get involved with something that ultimately is not a good fit for you. It just doesn’t make anybody happy to get somebody sort of signed up and enrolled in a study that is not a good fit. We want people who understand the process and understand what we are trying to do because if—you can always drop out of a clinical trial, but you would have wasted your time, and that stuff, so it’s always better to go in with good understanding of what the study means. And so, that said, I think the—maybe the two most important things going into it are trying to get an understanding of what the expectations of you would be if you wanted to participate. What I mean by that is that many studies are more rigid and more rigorous than your standard clinical care—in other words, they may have you coming back for follow ups more frequently than you otherwise had been. And it may sound like a great idea to participate in a new study for a new treatment, but when it actually pops up on your calendar and you’re having to get yourself back and forth from the doctor’s office more frequently, then that becomes less desirable. Number two would be an understanding of what the treatment is and what the possible treatments are, because sometimes there are comparisons. A follow-up question to that would be, are you going to know what the treatment is? One thing we haven’t talked about yet is that you may be randomly assigned to a treatment, and I would say that most of the time that’s the most common design for these type of studies, and trying to learn a little bit about that and what that means and chat with them because we are not—that’s also outside our standard of care. If the doctor prescribes an antibiotic for a pneumonia or something like that, you aren’t being randomly assigned to antibiotic A and antibiotic B, you’re using what your doctor decided was the best choice for you. And so, this is different from that, and trying to get a sense from the investigator or the coordinator what that means. The question that you’re most going to want the answer to and the doctor is going to have a hard time answering is, does this medicine work, and is it going to work for me? And if you have reached that point, and you’ve reached that question, then you are really starting to understand what clinical trials are about, and if you can understand that the doctor—by definition, at this point, they probably don’t know. They don’t know if it’s going to be better for you than what is already out there, and the point in participating is to help everyone learn the answer to that.

GUY EAKIN: Well let’s talk about that randomization. Certainly at BrightFocus we receive applications for research studies, and one of the things that I see often is that some trials these days are starting to offer all the patients the investigational drug at different times, and so perhaps you’re on it in the beginning and off it at the end, or vice versa. How frequently do you see that happening in your area of the world? Is that something that is happening in smaller studies or larger studies, or is that part of the conversation you hear at conferences? How would you characterize that?

CHRIS BRADY: I think that we all want trials to be smarter, to be better, we want trials to be more efficient. So we do have these study designs that are not the traditional thing that we’ve been talking about so far and where people may cross over from one treatment to the other. And I think those provide great value in a study like that, I think for it to be valid and to produce good scientific results that we can all believe in, the order needs to be random. So you’re still not going to necessarily get to know or decide which one you get first, and you have to think real carefully about—and again, this is probably more for researchers and people using these types of study designs—there can be some pitfalls, but technically they may need to be larger: they can be more affected if people drop in and out of these studies. These are technical things that are probably more interesting to me and people who are doing these studies, but they are out there. And I think that innovation in these designs is a great way to potentially to make them more appealing to people, because maybe an individual would say, “Well I’m not going to be in this study for 3 years and you’re giving me a sugar pill, I’m just not going to sign up for that. Based on a flip of a coin, that doesn’t sound very good.” But maybe an individual would if it was a sugar pill for 3 months and then an active pill for 3 months or vice versa.

GUY EAKIN: Well that sounds like certainly a question to have with the study coordinators or the investigators that you have a conversation with. One of the things that we haven’t touched on is that feedback back to the person who usually is caring for your eyes. How does a typical clinical trial coordinate your care with your regular eye care provider during this time where you’re enrolled in the clinical trial?

CHRIS BRADY: That is a great question and would certainly add that to the list of questions to talk about with the study coordinator or the research or the study doctor, because frankly, I don’t think there is a set answer to that question. I think that sometimes the study doctor is your main clinical doctor that you see from time to time. That’s certainly the way it is here at Hopkins a fair bit of the time, but many times it’s not, and so you hope that there would be an open line of communication to let the primary doctor know, “Hey, Mr. Jones is signed up to participate in this study for macular degeneration, I’m going to be following him frequently for these study visits.” And it’s nice to let them know what the possible treatment assignments are: in other words, “Mr. Jones is going to be randomized to receive either treatment A, which is a new experimental treatment that we are testing against the standard of care, or the medicine that we would normally use in standard practice.” A lot of times that doctor may want more information: “Okay, well, which drug are you giving him?” But again, that information is sometimes sort of kept a secret, or what we call in research “masked,” so that people don’t know exactly what treatment assignments they are getting.

GUY EAKIN: Well thank you. So with—certainly a lot to keep in mind—all of this in mind, I’d like to go ahead and segue into the question and answer portion of our call. And we have had a few people calling in and leaving their questions with us. Before we move into that, I just want to take a moment to thank everybody who has listened today and submitted questions. And with that, we would like to take the first question from Katherine from Arizona, who is asking something we hear about so often, which is about stem cell treatments, and what’s involved in stem cell clinical trials and—I might extend that—and what do you see on the horizon for stem cells and macular degeneration?

CHRIS BRADY: Yea absolutely. Stem cells are very much a hot topic. Just to back up for a second, stem cells, by way of background, are cells in your body that essentially can turn into any type of other cell in the body. And so the thought process is, if you have a disease that is causing some damage to cells in your body, like macular degeneration, and those cells are damaged, well, couldn’t you use the stem cell, and either tell it or encourage it to become a retinal cell and essentially heal itself? So I think theoretically it’s a very appealing way of approaching disease in the eye and throughout the body, and so there are investigators that are working on stem cell therapy. These types of treatments are in earlier phases of development, and some of the stuff we have been talking about so far, smaller groups of patients, these studies—again since they are, I would say, more experimental—since it’s a whole new topic, it’s a whole new domain, it’s not, as I said before, a chemical or something like that. We’ve been working with chemicals in medicine for 100 years. This is a whole new world. Therefore, things like the risks and stuff like that and the benefits are not as well characterized. Many of these treatments are more complex than just taking a pill or something like that. They may involve surgery, they may involve injecting the stem cells into the eye or even under the retina. I think it’s a very exciting domain. It’s, like you said, very much a hot topic. People want to know, it is something people talk about in meetings, and as we move forward it’s something I’m very interested in hearing more results from.

GUY EAKIN: We had a listener write in, “What if I’m participating in a clinical trial and want to get out?” What do you do then?

CHRIS BRADY: That is such a great question because, like I said before, you never want to feel trapped if—in many ways you are a volunteer: even if you got into it thinking this is a way to treat your own disease or for your own personal benefit, you are a volunteer, you are a volunteer for science, you are a volunteer for the drug company and really for the whole population of people with this disease, and so you can always drop out. That is a fundamental, ethical rule of clinical trials. Now the investigator may ask you, they may say, “Listen, I totally understand, can we do one more visit to just collect better information on why you want to drop out, do one more examination?” because let’s say, for example, you want to drop out because you’ve had some side effect, and if you say, “I just want to drop out,” well if 100 people all drop out of that study and it’s all because of the side effect, and they don’t get a chance to write that down and send that information back to the FDA, we could be missing important information. And so, let’s say you are in a clinical trial and the team asks you, “Please come back in one more time,” I would urge you to do that. It’s not because they are trying to talk you back into it or keep you in the study, it’s just so that we can make sure that we understand why you’re dropping out and making sure we aren’t missing something.

GUY EAKIN: All right, thank you. Well, let’s move on to the next question, and actually this one appears to look directly into your line of research that you’re doing at Johns Hopkins. Mary from Illinois asks if Dr. Brady recommends the use of Amsler grids at home or the newer electronic devices, and what’s the best way to check the eyes in the home? Do you have an opinion on that? I’m guessing that you probably do.

CHRIS BRADY: Well I do, and it’s a great question. It boils down to something that we haven’t talked much about yet, which is who can most benefit from any treatment, whether it’s a new treatment or our standard treatments? And you can do a clinical trial of an Amsler grid, you can do a clinical trial of a diagnostic test, and that has been done. So, we’re referring to a device that can be used at home to check the vision, check whether there is new distortion in the vision, and maybe a sign of worsening macular degeneration. I personally, in my practice, encourage people to check their vision. I usually will ask them to do it once or twice a week, sometimes more frequently, and I sort of have a conversation with the individual patient about what is the best way for them to do it. One way that we mentioned is something called the Amsler grid, and that’s just a fancy grid of black lines on white paper, and there’s other ones that are red or vice versa, and there are these other fancy techniques. And I will also tell people, if you don’t have that available you can look at a piece of newsprint, you can look at blinds, something that has a repeating pattern. The key is to check the two eyes individually, check the vision in each eye, separately, and that is to really drill down because the brain is smart and it will cover up a problem in one eye if you’re looking with two eyes. I think either is appropriate, and again, I have a conversation with the individual to see what’s best.

GUY EAKIN: Well thank you so much. I think that seems to be about all the time we have today, and I want to thank everyone involved in the call, certainly Dr. Brady, as well as all of our callers and question askers. Thank you so much to everybody for taking the time to be part of the conversation. Our November chat will be on Low-Vision Resources and Services. We encourage you to register and submit questions in advance, and we will be sending you a reminder email. And you can always call us at 1-800-437-2423 for any questions you might have about macular degeneration as well as the other diseases that are within our organization: Alzheimer’s disease and glaucoma. You can always find our resources on our website at www.brightfocus.org. Thank you again to Dr. Brady for helping us to understand clinical trials better, what the challenges are of getting involved, what the questions are that we should be asking, and what the benefits might be for any patient who might be interested in participating, as well as the benefits that are out there for our world to better understand and treat macular degeneration. Thank you from all of us at the BrightFocus Foundation. Have a great day!

The information provided in this transcription is a public service of BrightFocus Foundation and is not intended to constitute medical advice. Please consult your physician for personalized medical, dietary, and/or exercise advice. Any medications or supplements should be taken only under medical supervision. BrightFocus Foundation does not endorse any medical products or therapies.

1. BrightFocus Foundation, 1-800-437-2423, or visit us at www.brightfocus.org.
2. What are clinical trials?
3. The phases of clinical trials
4. Antidote (Clinical Trial Search Engine)
5. Clinical trials information at www.clinicaltrials.gov
6. Amsler grid to evaluate vision changes at home