Well, I'm Dr. Jim Del Rosso, a dermatologist in Las Vegas, Nevada, where I'm Research Director and Principal Investigator at JDR Dermatology Research and also a Senior Vice President for Clinical Research and Strategic Development at Advanced Dermatology and Cosmetic Surgery based in Maitland, Florida. I help them administratively with organizing clinical trials and also an Adjunct Clinical Professor of Dermatology at Torrey University, Nevada, and also a previous Board Member of the American Academy of Dermatology. That brings us to the group that we're talking with today. I'm participating here and very thankful to be asked to be part of the clinical trials course that is available to the American Academy of Dermatology. And I've been asked to talk about practical points in acne and rosacea clinical trials. I don't only do clinical trials in acne and rosacea, but certainly I'm involved with a lot of those trials. So here is a nice picture of me from years ago. I guess I still kind of look the same, fortunately. Hopefully you agree it's a nice picture and there are my affiliations. So we're gonna be talking about both acne and rosacea, but need to recognize upfront, they're lumped together very often historically, but they are uniquely different. They're as distinctly different as plaque psoriasis and atopic dermatitis. So there are certain points that I think are applicable to both acne and rosacea studies. Research investigators, they incur different responsibilities and we have to recognize the responsibilities that are very different than when you're seeing patients in clinical practice. When you're seeing patients in a research study, you're not seeing a patient coming in to have you decide how they should be treated. You're bound by what's in the protocol. Of course, you're looking out for the welfare of the patient. You wanna make sure they don't have any adverse events, but the primary responsibility is to collect the data that's mandated with the clinical trial. So the practical points applicable to both acne and rosacea studies is to really look at the study and understand the actual study population. It could be a subset of patients that have a particular disease state. For example, with rosacea, often you're seeing patients that have papules and pustules of rosacea, which is one category of rosacea, as opposed to patients that just have the background vascular erythema and don't have papules and pustules. And the same with acne. Are you seeing predominantly nodular acne? Are you seeing patients that primarily have inflammatory papules and comedones with an absence of nodules? Are you looking at acne scarring versus primarily at acne or residual effects like post-inflammatory hyperpigmentation? And also need to look at the sides of the groups that are involved. Recognize that throughout the study, you might get amendment updates that have to be looked at and integrated, and everybody has to know about them. There is training that you're required to go through before you're doing the study, both the staff and the investigators. Then there's informed consent, which is very critical to pay attention to and make sure you have the most current version, because if there's updates, you have to make sure those are integrated in the study right away, or that's gonna be considered to be a major protocol deviation. And then what clinical features are being assessed and are any being quantified? So there are a lot of clinical features of different diseases. You have to recognize and identify what is the study asking for? And there's an investigative global assessment in most studies, if not all studies, certainly acne and rosacea have them. And it's important to recognize this is not necessarily how you do it in clinical practice. You have to follow the investigative global assessment as it's defined in the protocol. And when you go in the room and you see the patient, that's what you determine first. You don't count lesions, you don't palpate, you just determine the investigative global assessment. You document that and it doesn't change. After you do lesion counting or evaluate other assessments, you don't go back and change the investigative global assessment. That's the visual gestalt. And then there's an investigative meeting, right? And this is on your time. And this is where you have to listen in, either attend the meeting live or virtually, or have someone do it with you virtually over the phone or come to your office. And it's important to really pay attention and identify nuances and study methods with each trial because from trial to trial, they can have major differences. Make sure you clarify any issues or concerns that may come up. Like if you're allowed to intervene and utilize another type of treatment during a study, are you limited in what type of cleansers and moisturizers that can be used? If you have to stop a treatment, if you're allowed to according to the protocol for a certain period of time. And then when you're looking at the training, you have to make sure that all the required trainings are completed by the principal investigator, the sub investigators that assist the principal investigator in the trial and the staff. And you're going to have monitors that come in. You have to remember in a clinical trial, unlike your chart notes, which may or may not be looked at by anyone word for word, everything that's documented in the clinical trial is looked at by at least three or four different people. And the accuracy is very, very critical. And the documentation is very critical. If you're asked by a monitor to change data or the method of how you're doing something, don't take that from the monitor. Make sure it appears in the protocol or you get a formal documentation that everyone in the study is to use that method because monitors have their own biases based on their own experience. It's not uncommon during a study for the monitors to be changed. Now you have a new person coming in that their pet peeve is something different than the person before. Remember, ultimately, if you're the principal investigator, it's your name that's on file with the FDA and you're ultimately responsible for what goes on in the trial. That's extremely important to recognize. And remember your staff needs to know that. You may have new staff that think they're doing the right thing because the monitor tells them, no, you should be doing it this way. Make sure that is vetted. You change nothing until you're sure with documentation. And I always push for, if it's not in the protocol, you need a protocol amendment if I'm going to change the method of how something's being done. I personally push for that. So the fundamental daily activities that can affect study outcomes, very often we're going to be using, in just about every patient, they're going to cleanse, moisturize, and in many cases use photo protection. You have to know in the study what is allowed. Some acne and rosacea studies, they'll actually supply the actual products you give to the patients. That's true usually if that company has them available to them within that company, or sometimes they'll provide them. Usually they don't. So there are some specifications where there are certain types of cleansers, moisturizers, and sunscreens that are not allowed. You need to know what those are. Very often they'll tell you, document what the patient's using and make sure they're using the same thing throughout the study, and it falls within certain categories and not others. You have to make sure that what they're using is okay according to the study protocol ultimately. If you are to provide that, you have to find out how you're going to invoice for this cost of that, and if there are any specific products that are recommended and what the usage instructions are for the subjects. So every detail needs to be vetted and documented. Make sure all your staff and investigators are trained and that you have the written documentation, the certificates to back up the training for that study so that you can show it to anyone at any time, that everyone involved in the study, and they are designated on a delegation log, and only those individuals are allowed to be involved in the study and see any of the information in the study. If you're doing studies in your office, you can't have things with the study sitting out open because not everybody's allowed to see any of the details. They're all highly confidential. They're only available to the people in the study. So be careful what's sitting out on your desk. Everything has to be kept just under the study center and then certainly locked up so other people can't get access to it. So there's certain steps. It sounds cumbersome in the beginning, but once you learn them, it's pretty much smooth sailing. And then the details on the study drug, right? The investigator product, right? The investigated product that's being looked at. The usage and handling of that product. So sometimes you're just educating the patient how to do it and how often they need to do it when they're at home, let's say once a day or twice a day, in reference to how they're cleansing and moisturizing. Sometimes the studies will ask you to have the patient apply the first dose in the office and being observed and educated on how to do that. If the protocol requires that and you don't, that is a protocol violation and that's gonna be documented. And then also reported to the Investigational Review Board, the IRB, that the studies are filed with. And you have to have that approval from that group. It's a third party group that's overseeing the quality of the study. The application details, the timing details. Sometimes there is a time of when something is done. Let's say the patient applies the medication in front of the study team or the study coordinator that's with the patient. And they may want something documented a certain time after. Like wait 10 minutes and then see if the patient's having any stinging or burning or something of that nature. All defined by the protocol. You have to make sure that timing is documented and it fits within the requirement of the study protocol. How the investigational study drugs are stored and everything that's used in the study is stored. Very important, if refrigeration's required, you have to have a refrigerator that's monitored, that's under lock and key with the study product. So it's not mixed with anybody's lunch or samples from the office. It's kept separately. And there's a monitoring device to make sure 24 hours a day, the temperature is maintained. Compliance monitoring. So in the studies of the patients are utilizing diaries. Now patients are often given iPads to use at home, have to be sure that they're putting that information in. If they're not, typically your staff is gonna be responsible for keeping track of that and making sure it is so that the study is followed. So there may be things that the patient has to report at home, right? Used to be done on paper, but now patients will typically have an iPad or something similar to report that information. And that has to be tracked within the system. Tube weighing, patients bring back their study drug. You don't know what it is. If it's in a tube of some type, often that'll be weighed to try to monitor for compliance. And you have to make sure that you follow the protocol into when study drug is returned and when new study drug is administered. It's all laid out, but everybody has to take the time to know how it works. And you may have three or four acne or rosacea studies going on, and they all could have different specifications, right? And then the document repeated the education of, I'm sorry, document repeated education at each study visit. So at each study visit, you're reviewing with the patient what they need to do, how they're using the medication properly, making sure they're telling you what they're doing so you could ascertain in the study document materials, what's called the source document, which is the Bible of everything that's occurred in that study that everybody's gonna go back to, including during an audit, that the patients have been educated what they need to do, how they need to apply the drug, when their next study visit is, and being sure that they have an open dialogue and ability to contact you if they're having any problems or questions. So when we look at acne vulgaris studies, you're gonna be looking at acne severity and grading that based on the investigative global assessment and the protocol, and be doing that throughout the study, and then also the type of lesion. So you're talking about open comodones, closed comodones, papules, nodules, and they'll often be defined. For example, in some trials, they define a nodule as being raised and firm, 1 sonometer or greater. Others are 0.5 sonomes or greater. So you have to define it according to the study protocol. And then documenting your anatomic location, being sure you're documenting sequelae that may be already present at baseline, so they're not a sequelae of that study at that point. The patient already had some preexisting acne scars. And then the color of the skin. Patients will often report their race, their ethnicity, but typically we're utilizing Fitzpatrick skin types or other methods of documenting the skin color. Now, be careful about investigator bias from secondary changes. If the study is evaluating the investigator global assessment, let's say of acne, and the primary focus is on the inflammatory lesions, the papules, pustules, and nodules, and even the comodones that are present. But you're visibly also seeing some old pitted acne scars and some dispigmentation. That is something typically in clinical practice we take into our mind in terms of the severity of acne. But if the study is not defining the severity based on those other sequelae, you have to block those out and be grading based on what the study is specifically asking for. That's sometimes hard to do. In the case of rosacea, it may be that you're looking at the papular and pustular lesions and not the surrounding erythema as part of the investigator global assessment. So, let's say the patient's being treated for rosacea, and now you're at week eight. And a lot of those papules and pustules are gone, and you're grading that they only have a few left according to the IGA assessment in the protocol. But they have a lot of that vascular background erythema, which is not supposed to be factored in with that investigator global assessment. It's hard sometimes not to, but you have to follow specifically what the protocol is asking for. In that case, let's say it's a 12-week study, and at the end, you have no papules and pustules, and the investigator global assessment rates that as clear, right? But you have pretty significant background erythema, but that background erythema is not part of the IGA, but you're visibly seeing it. And that patient has papules and pustules completely gone. They're graded as clear because the investigator global assessment in that study is not factoring in the erythema. So, it's very, very important to consider that because it's very easy for our mind to revert back to how we would grade the patients in clinical practice, which is not the way it's done in a study. The way it's done in the study is how it's defined in the protocol. And then the different lesion types, I already mentioned making sure you're looking at you know, the sizes, certain types of lesions, if they're defined in the study. Now, this is very important. In the case of acne and rosacea studies, you're typically going to be counting different types of lesions, and there's a required minimum number of those lesions. So, it's very important, the last bullet point on the bottom of the slide, develop a consistent counting method. Sometimes they ask you to count in different regions. Sometimes they ask you to count on the whole face. You have to know if certain areas are included. Sometimes on acne, the nose is included. Sometimes it's not. So, you have to know the areas that are included in that study. And then have a consistent method because it's easy to get lost and double count certain lesions. So, have a consistent method that you follow. As the investigator, the lesion counting and the investigator global assessment could not be done by your staff. It has to be done by the principal investigator and the sub-investigator. We often try to have both there doing it together because in case the patient comes back at another time and only one person is there, you have a consistency among the investigators on how they're doing the lesion count. So, you have consistency of data throughout the study. Most studies are going to ask that the same person is there at baseline and at the end of the study to assure that consistency. But going back to the caution, the second caution above, be careful about enrollment creep. Let's say the patient requires, the study requires that the patient have 25 inflammatory lesions, papules and pustules, and no more than two nodules. Right? So, you're counting and you get to 23. Right? It's very easy to say, okay, let me go count again. We're close to 25. Right? Recounting should not bring you to 25 or more unless the patient actually has 25. Enrollment creep is something we know occurs. It may not be intentional. Sometimes it may be intentional. It ruins the accuracy of a study if you're not counting the lesions accurately. And remember that the primary and secondary endpoints are defined in the study and we want to make sure that they're being properly captured. And then typically most studies are looking at static assessment where you don't care what the patient was like before. You're looking at them on that day. So, you're not necessarily going back and saying, oh, this is what it looks like today versus what it was like at baseline or four weeks ago. They're static assessments. But sometimes you are asked to do comparative assessments. Once again, this is all defined in the study protocol. Right? Now, in rosacea studies, many of the comments that I'm making are the same. They apply to rosacea the same way they apply to acne, remembering that you have a background erythema as a significant component of rosacea studies. So, in studies where you're primarily looking at changes in inflammatory lesions, papules, and pustules, they may ask you to do a clinician erythema assessment. And that's a gestalt of the overall erythema. So, that's going to include what telangiectasias contribute to, which you really can't sort out at that time. And that's fixed within rosacea skin. The background vascular erythema from the dilatation of the blood vessels, which is evaluated in some studies as persistent facial erythema, which is different from the perilesional erythema, the lesional erythema that's around the papules and pustules, that as they go away, that erythema will go away also. You may be asked to grade that overall erythema, and you certainly will do that in the studies that we'll capture that. Not all of them do. You also need to look at whether the studies are wanting you to count the papules and pustules. Are they asking you to grade or evaluate telangiectasias? That's important. And also, whether you're looking at the persistent erythema after papules and pustules are gone. That was typically done with therapies that had patients that had no papules and pustules or maybe up to two or three, because that's the only way you could look at the persistent erythema. I know this is a lot. It's worth looking at a couple of times and taking it in. It's all going to be defined in your protocol and your training. Everything else is pretty much the same. Same with the lesion counting. Have a consistent method and be careful of enrollment creep. So, now let's get to skin tolerability and adverse events. So, treatment emergent adverse events are anything that happens in a study. If the patient bumped their knee on the table and they tell you their knee hurts, that's captured. If patients, for whatever reason, are forced to go to a hospital, unrelated, they're in a car accident, they have a cardiovascular event, that's a serious adverse event that has to be reported immediately. It may not be related to the study drug or not. That's going to be in a separate category. That will all be defined. But in acne and rosacea studies, we're often capturing, and pretty much with all topical medications and sometimes with systemics, skin tolerability. But this is typically with a topical agent. So, those are separated out and you may be asked to capture the amount of erythema, the amount of scaling, the amount of swelling by different rating methods. And those are local skin reactions, skin tolerability reactions. They're not necessarily adverse events. Now, sometimes they will be captured as an adverse event if they reach a certain severity or there needs to be a certain amount of intervention or the patient had to stop the drug beyond the period of time, the study drug, or stop it completely. You have to know when your local skin reaction is also reported as an adverse event. And then if you do see skin tolerability reactions, what the protocol allows you to do to intervene. Are you allowed to reduce the frequency and still be within the study protocol to evaluate efficacy? Are you allowed to utilize some type of intervention? The protocol will define that. Some, if there's any intervention, that patient's going to be pulled out of efficacy assessment but be continued in the study for safety. So, this is a very important area to evaluate how local skin reactions are captured and what is allowed or not allowed before the patient is taken out of the efficacy pool to be evaluated. And then adverse events, you really need to know what's been present at baseline. You know, if the patients have their skin burns or stings a lot even before they're entering into the study, it's important to have that identified. But also, is the patient telling you something happened or is it something that you're observing at the visit? So, that differentiation is very important. And then there's definitions of severity. You go by the study protocol. The serious adverse events, as I mentioned, will be defined by certain levels of intervention. And certainly, if the patient has to be hospitalized, that can certainly be for any reason. Now, when adverse events are occurring or local skin tolerability reactions are occurring, you have to make sure you document the start date and if that resolved or not. And then be looking at the relevance of the study drug. So, that's very important. It all has to be documented. Your staff has to be up to speed because a lot of times they're going to be discussing that with the patients. And then there may be special interest adverse events where they define certain characteristics that they want to find out, is this related with this particular drug? So, did the patient have some other type of eruption that you're looking for or some type of tolerability reaction that you're specifically wanting to capture? And those are captured separately, but that's all defined in the study protocol. And then the documents that you use to capture all the details in the study should have that defined, right? So, all of this, if you're doing it for the first time, it takes a little while to wrap your head around it, but it's important to pay attention to it and be consistent. So, I tried to give you in a hopefully a relatively short period of time, but something that you can listen to over and over again if you're just learning. What I have found over the years to save me a lot of trouble when I'm doing these things preemptively and making sure we're doing it right from the outset, then to go back later and have to clean up a mess that I may have created, which we certainly want to do, don't want to do in clinical studies. We want to be preemptive. So, thank you very much. And I really hope this was helpful to you. And I appreciate the Academy's confidence in me and educating my colleagues about acne and rosacea studies and how to best perform them.

clinical trials

acne

rosacea

dermatology

protocol adherence

research investigators