 Just to start with a definition from more of a regulatory perspective is that this clinical research is a systematic investigation, including development, testing, and evaluation designed to contribute to generalizable knowledge. And the things that I wanted to point out in this definition are, number one, that it is systematic. So when you're talking about doing a research project, it requires some forethought and some planning. You've got a hypothesis. You're going to review the literature, look for things to support the reasons why you're doing your research, come up with criteria for your protocol, what kind of patients you want to enroll, even if you're doing retrospective research, specifically what patient population do you want to look at that would help you answer your question? And the next aspect of that is that it contributes to generalizable knowledge. So really what this means is that that separates research from your standard care medical practice. When you're in, you know, in clinic, you're looking at the patient who's right there in front of you, how you can treat that individual patient. When you're thinking about a research project, you're looking at, as I said, a group of patients, a patient population, and treating individual patients is not really the focus of a research project. I mean, ultimately, you know, yes, you want to improve patient care, but really you're looking at a larger, a larger issue. And so for clinical investigators, this is sometimes a difficult, a difficult challenge. I mean, a kind of a balance between, you know, your usual, your standard medical care as a medical provider versus a investigator. And beyond just the scope of treating an individual patient versus treating a patient population, what works better in a population, say, of glaucoma patients as opposed to this specific patient in the chair in front of you, it changes your relationship with that patient. And I think that's the significant part that clinicians often have a difficult time dealing with, because as a clinician, the patient comes to you for your expertise, of course, for you to tell them what you feel is best for them. But when you're in a research investigation, you're really partnering with that patient, right? You're asking them to help you participate in your research to, you know, to share, you know, their information with you for this larger question that you have in mind. And so, when we talk about regulatory requirements for research, it's really because of this different relationship that you have with this patient now, when they're a participant in your research study versus the patient in the clinic. So to be, before I get into, so it's a little bit about what research is just in very general terms, but just off the top, I'll eliminate some things that research is not from a regulatory perspective, quality control. For example, we've certainly seen research projects come through our area. For example, I think it was Brian Stagg, who did one looking at fellowship programs or, you know, residency programs, sent out a survey to other programs outside of Utah asking specific questions about how their programs were structured and looking at different, you know, satisfaction with, you know, certain aspects or part of the curriculum. Really the IRB didn't consider that research, per se, or clinical research. I mean, certainly it's a type of research, but it really was kind of aimed at, you know, improving a process. In surgery, they do QA projects all the time. You know, how do they improve their instrument sterilization or their processing or something? So that's not really considered clinical research. Case reports, the common question. A lot of you will probably be publishing case reports. And really the IRB, it seems a little random, but they have defined a case series of three or fewer patients as not requiring regulatory oversight from an IRB. So just a couple of case reports, you can go ahead and publish and not really couch that as research. If you have any questions anytime, just haul around. Another topic that is not considered research, and it's kind of a, hi Renee, a gray area is off-label use. This is strictly defined as using a medication or device within the practice of medicine. But you're using it in a way that deviates from its FDA product labeling. And if you've ever had the pleasure of reading a drug or especially a drug package insert, it's really a wealth of information. And it tells you not just the, you know, the condition that this product is approved to treat, but the patients that have been studied, what their adverse events were, essentially gives you all of the data from the phase three clinical trials that went into and the preclinical information that went into getting this product FDA approved. So the FDA realizes that labeling can't address every situation that comes up in clinical care. So off-label use, it's legal, it's very common, and I think the caution is that the farther you deviate from the approved uses, the more risk you run when you're using things off-label. Specifically, you don't know risks and benefits as well as you would in that approved patient population. There is no regulatory requirement from a research perspective for off-label use, but in conversations that I've had over the years with risk management here at the university, they really do suggest that you do a thorough informed consent process with your patients. And again, you know, it depends on how far, you know, you're deviating from the approved use, but actually on the FDA's website, there is a page for patients as well as providers, and they're very, very brief, but basically it tells the patients, these are some questions you should be asking your physician if he or she mentions to you that they want to use a drug or device for, you know, that particular indication. It just talks about, you know, what questions you're asking, what are the risks, what are the possible benefits for me. So again, off-label use isn't considered research, however, it can quickly become research. We've had instances you can imagine during surgery, Dr. Crandall is constantly innovating the way he does his surgeries. A few years ago, he started adding, I don't know, ketorolac or something into his, you know, irrigating solution and a resident, which he can certainly, certainly do, under the practice of medicine, and a resident came to me and said, well, we'd like to compare, you know, adding the ketorolac into the irrigation solution with some other product, like giving it, you know, giving the eye drops post-operatively, and at the time there was actually a pharmaceutical company doing exactly that phase three study. But when you're, when you're focused, if you go back to that, one of those earlier slides when I talked about treating the patients in front of you versus a larger research question, when your focus becomes, you know, is it better or advantageous in some way or more, even more cost-effective to put this medication into the irrigation solution versus giving it to patients in eye drops, then you've got a larger question, and it does quickly become research in that regard. And the FDA and the IRB would require you to obtain what's called a investigational drug, new drug application or investigational device exemption in the case of a device to, to actually do that study. And what that means is they are giving you sort of their blessing to, to study this particular question for an indication other than which it's currently approved. So we can help with those things, but just kind of FYI, keep it in your mind, you know, when you're posing, when you're looking at your research questions, exactly what your scope, what your scope is. And again, it's a gray area sometimes, and I think what's, I hope we can, our, our research group, our clinical research administration office can help is answer those questions so that you don't have to wonder, you can come to us and say, do I need an IRB approval to do this project or, you know, or not, and we can help advise you on that. But there are things, you know, within the practice of medicine that, you know, you obviously are not regulated. You don't regulate surgery, surgical techniques. You can regulate the drugs you use. You can regulate the devices that you use during surgery. This was just one example when cataract surgery, which is obviously constantly involving, but made a major leap forward going from doing retro bulbar anesthesia for patients to topical. And at the time, even though, you know, surgeons could certainly go ahead and do that, and surgeons were doing that across the country, around the world, but Dr. Crandall felt it was important to actually do a research project on this and compare pain levels and patient compliance during surgery, comparing retro bulbar injections versus topical. And Tom Burns, TA Burns, was the anesthesiologist working at Moran at the time. They designed these trials. We did IRB approval. And they had several publications that came out of it. So I think, you know, it's fine to do whatever you want to do and innovate when, you know, in your patient population. But if you want to have a broader impact, I mean, and that may be where some of your motivation comes from. You want to publish, you want to, you know, change the field, do a research project instead of just, you know, innovating with your patients. And so obviously, again, you know, you know what a human subject is, but basically a few points that are significant in this definition is that it involves a living individual using data from deceased individuals using donor tissue. That is not considered human subjects research and it's not subject to IRB regulation. Obviously, when families donate loved ones tissues, they sign a lot of consent forms for that process. And that includes the possibility that that tissue may be used for research. If you're using information strictly from decedents, you don't need an IRB approval for that. You know, not as far as the IRB is concerned. Certainly as far as the IBank is concerned, but basically if you're using donor tissue, it would be considered a non-human subjects research project. And it involves data, either obtaining data through intervention or interaction. It's sometimes a little confusing. You say, I am not going to treat a patient. Why do I need approval to do that? If they're just coming in for their standard of care visits and I'm going to collect their information. Well, that's obviously a minimal, you know, a low risk project because they're just having standard care procedures. But nonetheless, you are obtaining their data and probably their PHI as well. So it does fall into the category of a clinical research project, which does, you know, fall under the regulations accordingly. Okay. Why is clinical research regulated? I guess it's like everything else because there are people who abuse privileges or, and I think the most famous study I always have to show it, even though I'm sure you're familiar with it. Just because it's so appalling every time I read these statistics, you know, just from this very start, the fact that it took play, this Tuskegee civilist study took place over 40 years, you know, in the United States. It wasn't something in the Middle Ages or the Dark Ages, you know, 1932 to 1972. You think we would have been fairly evolved by then socially that this sort of thing couldn't happen. But nonetheless, these researchers, and it was with the, the National, the U.S. Public Health Service. I mean, it wasn't some, you know, some small group of researchers in a lab in some obscure little town enrolled these 600 impoverished chaircroppers, most of them African American, comparing folks who developed syphilis versus those who did not. And their impetus was that they received free medical care, meals, and burial insurance, which that's kind of sad incentive, but nonetheless. Then, of course, the, you know, the transgressions just get worse from there. They weren't told their diagnosis, and they weren't treated, even though penicillin was established as the standard treatment for syphilis in 1947. That group still was not treated. Hard to imagine that this went on, but of course it did. And that's one of the reasons why this regulatory structure around clinical research mushroomed in the United States. It sort of began with the National Research Act in 1974, enacted by Congress, which established the National Commission for the Protection of Human Subjects. And part of this act, in addition to establishing this body, this committee, established basic principles underlying the conduct of human subjects research, and required that guidelines be developed to assist investigators in complying with those principles. So the landmark sort of report that came out of that commission is what's referred to as the Belmont Report. And what I find interesting about that, when you see how the regulatory structure has really mushroomed, and I'll show you just an example of that in a couple of slides, it's really all based on three very basic principles, and they really are basic respect for persons. As I mentioned, when you're in that relationship with a patient as a research participant versus as a patient, you're all well trained on how to deal with patients, how you deal with them respectfully, and not just in an informed and beneficial manner. But obtaining informed consent is one of the, probably two of two key areas of regulation in clinical research. So that relationship that you have with your participants, you're asking them to participate. They're under no obligation to, and they shouldn't be coerced to participate. Protecting their privacy, we all familiar with HIPAA, you know how that ties in. Beneficence, and really that means maximizing the benefit to risk ratio when you're designing your research protocol. It doesn't mean that you can't put patients at risk. You know whenever we're doing a clinical trial and we're offering an alternative to Lucentus or ILEA for treating CNV for example, you know, patients have to question, well here's an approved treatment and we know what the results are. Why would I want to, you know, try something that's not yet quite as proven, but again with thorough informed consent and they, by that point, you know, the investigators have enough data that they can say the risk is worth the potential benefit to these patients to participate in the trial. And justice, the third principle under the Belmont report, speaks to the vulnerable subject populations as evidenced in that Tuskegee study. But certainly other vulnerable populations would be considered pregnant women and their fetuses, children in general, prisoners, you know, those with not limited mental capacity to understand what's going on with the research. So some additional protections for them. So when I mentioned how the regulatory environment has mushrooms since 1974, here's just a real, and the second page of an org chart of all the offices under the Department of Health and Human Services. And then within that office, within that department, there is an office called the Office of Human Research Protections, OHARP. And that reports to the Assistant Secretary for Health. And the charge, the charter for this office is to do those things that the Belmont report and the National Act in 1974 mandated in terms of developing the principles and providing the guidance on clinical research for investigators. In addition to informed consent, which I mentioned, was one of the key principles underlying the clinical research regulations. What's called the common rule is the other. This is found in the Code of Federal Regulations. That's what that .45 CFR is. And it talks about review of clinical research. I think you're all familiar with what an IRB is, essentially. But that was really defined with this act. The membership of the IRB, who can sit on the IRB looking at different backgrounds of the members and showing that they don't have any conflicts of interest with the research that they're reviewing and setting out quite a lot of criteria that the IRB has to follow for approving a research or disapproving a research project. Here at the University of Utah, the IRB reports to the Associate VP for Research Integrity, who, of course, reports to the VP for Research. The Associate VP for Research Integrity is Jeff Botkin. And I know he's going to be speaking at a Grand Rounds next month, I think. And Jeff actually sits on this OHARP. And I can't really read it somewhere. Down in here, there is an advisory committee to the secretary. And he is currently the chair of that committee. So he's really tied into what's happening nationally with trends in regulating clinical research and providing guidance, really, for those regulations. The IRB, if you haven't yet had the opportunity to help to create a project, their website, the IRB website is very informative. It has guidance series. It has templates of documents that you would need. It explains what's required in the IRB application. And then the IRB application itself is a web-based system where you no longer have to come up with volumes of paper. And it leads you. It's a Q&A. You really don't even need to write a protocol in advance, although they do suggest that you do an outline. And really, one of the beginning slides that I showed talking about a systematic investigation, it lists all of those kind of things that you're going to want to think about that the IRB application will ask you in terms of background rationale, your patient selection criteria, your recruitment, your procedures that they're going to undergo and how you're going to analyze the data. So this is all online. And our regulatory coordinator in my office can help you with that. You will need to register real quick registration with the IRB as well as do some online training in human subjects research before you can submit an application to the IRB. So as I said, the National Research Act defined the criteria that IRB uses for approval. And as I mentioned, one of the big ones was that beneficence, assuring that the risk-to-benefit ratio, excuse me, was favorable. And I think that's obvious to people from a patient care perspective. But the IRB actually also looks at your research design in terms of whether or not it will answer the question that you're asking. And they look at that also because they don't want you subjecting patients to procedures or even evaluations if they're frivolous, if they're not related to the question at hand. So again, your project might be considered either a minimal risk to a high risk, but nonetheless, if the potential benefits to society, to patients in the future justify it, that's OK. Again, I guess I just said that. Selection of subjects is equitable as something else that we'd look at to just ensure that your protocol isn't biased and not going to give you results that are generalizable to a larger patient population. Informed consent is a big one. I'll talk a little bit more about that in detail. But not just obtaining it, but documenting it. In research, a lot of these regulations are similar to quality assurance, which is done in manufacturing, in labs, excuse me. And it's basically, if it's not documented, it didn't happen. You might have a patient's consent, but if it's not documented and you can't prove that you have that consent, that's not going to help you a whole lot. The IRB does have situations where you can obtain verbal consent from patients, but then, of course, there's a process for documenting that. Yes, in fact, I did obtain verbal consent from the patient on this particular day. Monitoring the data, the most obvious thing that you're looking for are any bad experiences that patients have during your research project and reporting that. I think one of the things that I value most within our group of our research office as well as at Moran is that we really do strive for transparency. It's always worse to not report something than to say, this happened, and just put it out there, and you deal with it, and you manage it appropriately. It's always 10 times worse when you're down the road and someone comes back and say, well, you had this event back here, and it wasn't reported, but yet you continued as if it didn't happen. And so oftentimes, it just requires modifying the way you're doing your study a little bit or maybe not. But nonetheless, it's sort of like that old adage, there's no stupid question, just not asking a question. It's the same thing, I mean, reporting anything that happens with your project, even if it's not out, I've lost the consent forms, document it. I mean, so it just shows that you're really doing a good job of trying to do your research appropriately. Protecting the privacy of subjects, maintaining confidentiality of data. In these days of HIPAA, I think we're all familiar with that. The vulnerable patient populations, I mentioned. And then for the consent document itself, it looks a little daunting, but these are the types of things that are generally covered in the consent and required to be covered. The rationale, the background of why you're doing this project, what is the purpose, what is specifically the research question you're trying to answer, what procedures are patients? Should patients be expected that they will undergo? And even if it's you're obtaining data from their standard care, you want to tell them that. We're going to be obtaining data from your eye exams. And then in the consent form, we highlight specifically what is done for their standard care versus what is experimental or research in phase three trials. You collect a lot more information that is primarily safety information than you would in clinic. You're seeing patients more frequently than you would in clinic, probably. And so we let patients know, before they even enter the study, you'd only have to come in once every three months if you were seeing your doctor for this condition. But we're going to want to see you every month. That impacts whether or not they can participate. But they know upfront that it's going to require a little extra effort on their part, for example. What are the risks and the benefits of your project? Are there alternatives for patients? Is there an approved therapy or isn't there confidentiality, voluntary participation? And then we give them information on the doctor's phone number and who they can contact at the university if they're concerned about the way the research is being conducted. There are other things, depending on the magnitude of your research project, that you would include in a consent document. But again, the IRB website has a template that gives you all of these headings on there. And you can just decide whether these things are applicable to your project or not. One thing, when you do not only does a patient have a voluntary choice to whether or not to participate in a research project, they can withdraw from a research project at any time without any consequence to them. I think obviously there are situations where it's not in a patient's best interest to withdraw from a study because of the increased surveillance that often goes along with the research. When you're studying a new drug that's maybe not quite as significant because you would probably stop the investigational drug. But when you're doing an IOL study or any other type of implant, you could imagine that implant is intended to stay in that patient just because that patient says, I don't feel like coming in for follow ups any longer. Doesn't mean you're going to take the lens out or the knee implant or whatever. They still have what is essentially an unapproved device implanted in their body. So it really is in their best interest for them to stay in the study. But nonetheless, you can't require them to do that. All you can do is give them all the information and what the consequences may be of withdrawing. As you're doing a research project, if you learn some new information, again, if it's about a drug or a device in particular, but say those adverse events that we're seeing in the project are telling you there's some concerns with maybe using this product on a specific subpopulation of patients or something, you're required to tell patients that. If you have significant enough findings, they need to know. And they may need to reconsider whether or not they want to continue in that project. And we've had we've seen situations in clinical trials where the information is significant enough that the IRB will require you to re-consent patients just to document the fact that you've shared this information with them and they've agreed to continue nonetheless. OK. There are some other situations where that full consent is not required. However, there are options where you can have a waiver of consent or a verbal consent. A lot of our residents and students do questionnaires with patients. If you are sending a questionnaire, you have a little cover letter explaining what you're doing and send a questionnaire or have the patients call you to complete the questionnaire. The fact that they are agreeing to answer those questions implies that they're consenting to participate in your research, but nonetheless the IRB will want to see that cover letter and the questionnaire upfront that shows that you are explaining to patients what you're researching. And a whole other set of issues when you're dealing with minors, we get into ascent for children who are typically between the ages of seven or 17, but generally they feel are able to agree to participate of their own accord. And that's actually pediatric clinical research over the last couple of decades has become much more heavily scrutinized. Because if you could imagine, a lot of that off-label use, which is still out there, but involved using medications in children that were not studied in children. And the reason that they probably weren't studied in children, because that's a real vulnerable group. It's a real risky group. When you've got little human beings developing and you're going to throw an investigational drug at them, what kind of consequences is that going to have long term? But eventually the FDA realized in their wisdom that that really probably wasn't in their benefit in the long run. But nonetheless, unless a minor has a situation where they need an investigational treatment to sustain their life or to retain their vision, for example, they actually do have to agree that they're going to be willing to participate in the study, even if they don't understand. The parents still have to consent, but the children have to ascend that they're willing to participate. For patients are required to have a consent form in their native language. And there is a translation service on campus that will, for a very reasonable price, translate consent forms for us. And for us in ophthalmology, visual impairment is an issue with reading a consent document. So we'll either make our consent in a large font so that visually impaired people can read it, or you may have to have a section in there where you're allowing someone to read the consent to the patient and signing that they witnessed the process and that the entire form was read to the patient. In our investigator initiated projects where we may not have a professional clinical research coordinator helping you with them, we've just added this little four check boxes to the consent form to really to help you or the staff, whoever is helping you with recruiting patients for your study, kind of as just a reminder that you've really conducted the consent process, not just here's the consent form, sign it and we'll take these other pictures, which really does happen quite a bit, but you actually had a conversation with the patient about what the research is, why you're doing it, what they have to undergo, and you really should be asking them, do you have any questions about the research? And so these little check boxes that we've added just as a reminder to say that you've reviewed the nature of the research, you've given the patient time to consider it, ask them any questions and answer them if they had them. And finally, the patient should go home with a copy of that signed consent form, so they have that for future reference. Oops, excuse me, I know you're all familiar with HIPAA from a healthcare setting, but any research, HIPAA also when that law was enacted, required that any research involving protected health information be reviewed by a privacy board, how other organizations handle that, I'm not sure, but here at the University of Utah, the IRB does act as the privacy board for research with PHI. And then as you're familiar with authorizations as well, in clinical practice, authorizing to disclose a patient's PHI for some reason, whether it's to their insurance company, to a referring physician, whatever, that applies to research as well. So actually the consent form is a consent and authorization document usually because there's another page tacked on to the end of that consent, which is just about the authorization telling the patient what information we're gonna be collecting about them, what we're gonna do with it, who we might show it to, who we might share it with, who we won't. As you know, there are 18 patient identifiers defined by HIPAA. A lot of investigators nonetheless still feel that if you don't have a patient's name on the data, then it's de-identified, and not necessarily. You know, if you've got their date of birth, if you have their dates that you've seen them in clinic, their dates of service, something like that. So you may be in a situation where you think you've got, oh, I've got de-identified data, I can just share this. Well, it may be a limited data set rather than de-identified data, and that's another area of regulation. And so, as I mentioned, we're obtaining authorization from research participants, not just consent for the research. And if you do have a de-identified data set or a limited data set, and you're doing collaborative research with investigators at other institutions, there may be some agreements that you would wanna put into place, institution to institution. And the IRB and our regulatory office can help you figure out which of those you need as well. There are some types of research. Besides those things which I said were not research, like case report forms, like off-label use, there are things that are research, but they're considered exempt because they are so low risk. And that list, fortunately, has been growing as the federal regulations evolve, and they realize that IRBs are just overburdened by a lot of research that is much safer, much less risky than the amount of effort that's going into regulating them. And fortunately for residents, because you all do a lot of these things, are retrospective case reviews. So, not a case study, but a case series of all of the patients who have a certain type of IOL in their eye or something. But if you're just looking at retrospective records that could potentially be exempt from full IRB approval, the catch-22 is you have to submit an application to the IRB for them to tell you that it's exempt. But nonetheless, I think that application helps you structure your research. As I said, it is a Q&A process. It helps you develop exactly what your hypothesis is and how you're gonna test it, specifically what patient records you might be looking at. Really define it more than you might otherwise have. And normal educational practices are exempt. Collection of a blood sample might be exempt if a patient is having a blood draw as part of their normal care and you want a sample of that. That might be considered exempt, but I think now actually the regulations are becoming going the other direction when it comes to biosamples, especially because of all the genetic research that people are doing, obviously. And kind of the regulatory climate is now considering that a biosample from a genetic perspective can never really be truly de-identified. And so, I'm just getting another blood sample when the baby's having a heel stick for something is considered minimal risk but may still require full regulation by an IRB. This is what my office looks like. As I mentioned, we have five research coordinators, a technician who is trained in a lot of specific programs or visual acuity, you know, ETDRS visual acuity is a standardized research procedure as opposed to the Snellen charts, visual fields, different measures that have become more standardized in research settings than they are in the clinic. So she can help you with that. Actually here at Moran, the genetic counselor falls under clinical research, although she's certainly seeing patients in the clinic, but I'm anticipating that the state of genetics in the clinic, in ophthalmology, is certainly gonna catch up to where it is now, say in cancer treatment, for example, where you've got treatment decisions based on genotyping. I mean, obviously we have that right now with retinoblastoma, for example, but it's not as big a thing in ophthalmology, obviously, as it is in certain other areas, but that's gonna change. But right now, you know, we're enrolling studies that are looking at patients with specific genotypes. So we are doing genetic testing on patients. Brianna can help you pre-authorize testing, you know, with labs. She's got relationships with certain labs across the country, and obviously talk to patients about their condition, you know, what the genetic information is about the condition, and then when results come back, specifically explain those results to them. And our regulatory coordinator, Elizabeth, is absolutely key in all of the IRB applications, as well as implementation questions that come up along the way. And I think that was it in a nutshell, a quick summary of, I hope, you know, why we, what we do in clinical research, and why, any questions or general or specific? No? Okay, great. Well, thanks for being here so early, and definitely, you know, come by our office or give me a call, even if you're thinking about, you know, you haven't decided you're gonna pursue something yet, but I've got this idea, and, you know, we're always happy to give our opinion off our guidance, okay? Thank you. All right, thanks.