Hi, I'm Dr. Ted Lane. I'm a board-certified dermatologist. I am the chief executive officer and chief medical officer of Sanova Dermatology, and I also direct the Austin Institute for Clinical Research. I'm excited to present to you today on clinical research site operations. I started a clinical research site within my own clinic about 13 years ago and have grown it since then. And I think one of the hardest things to understand are the logistics behind a clinical research site and exactly what's required to get a clinical trial up and running. And that may be the biggest hurdle for people as they consider starting or getting into research, just not understanding the black box that research is in, since many of us did not learn this in residency or medical school. And indeed, I ended up learning it along the way. So finding some good people to help you is, of course, important, but hopefully this presentation will help alleviate some of your concerns and give you some insight into the clinical research startup process. This is me. Again, I'm a dermatologist that practices daily in a medical and cosmetic dermatology clinic, but I also see research patients as well. I run trials in medical dermatology, you know, psoriasis, AD, hydradenitis, those kinds of conditions. I also run cosmetic trials for new toxins and fillers and devices. I run trials in skincare as well. So I've developed a research site that runs the full gamut covering our specialty. So let me first go into clinical research site operations. And I have no relevant disclosures here. This is all based on my experience and knowledge. So the agenda is we'll talk about the roles in a site operation, understanding the standard operating procedures that you may need, and also how to get started in clinical research so that this can really start acting as a launching point for you. So what happens usually is you'll get an email from either a CRO, a contract research organization, which is a CRO is considered the middle person or the middle company between a sponsor or the sponsor being the pharmaceutical company, for example, that has a new drug that they are developing for a disease state and the site. And what will happen is that the sponsor or the pharmaceutical company will decide to work with the CRO and say, hey, we need you to help us choose the sites and get the study started up, run the trial. A lot of times they do the statistical analysis based on the data that is received from the trial and help write a complete study report afterwards. So the CRO is that organization which can really take the trial from the idea phase, help write the protocol, help run the trial, help deliver the CSR. They can do all of that or they can do parts of that depending on how much the study sponsor wants to do. But let's say that you get an email from a CRO or a sponsor asking you about, are you interested in a clinical trial in disease state X? They'll want you first to sign a nondisclosure agreement or confidentiality agreement before they transmit any confidential information such as the trial protocol, certainly just even small parts of the trial, they'll want an NDA signed before they share with you any idea or inkling an idea. So once you sign an NDA, they may share first a feasibility questionnaire or a feasibility questionnaire with a synopsis of the protocol or sometimes the entire protocol is shared at the same time. And the feasibility questionnaire is really giving them an idea of whether you have the capability of running this trial or not. In other words, what's your experience in running a trial in disease state X? How many trials have you run in it? How many patients did you recruit per trial that you ran? How will you recruit for this trial if you were to be awarded the trial? Will it mainly come from your patient population or will you need funding to do outside advertising? Those kinds of questions. I'll also ask you if you have any competing trials in the same disease state. So all of that are some of the more common questions associated with an FQ or a feasibility questionnaire. And as you grow, you'll need someone to help you fill those out and that's someone who's called a feasibility specialist who can really handle all these inbound requests regarding different trials that are ongoing. So assume that you've received the feasibility questionnaire. You filled it out to the best of your ability. You sent it back to the CRO or the sponsor. They take a look at it. They may come back to you with questions about some of your responses and otherwise kind of look internally at all of the feasibility questionnaires that have been received and decide that, you know what, we'd like to move forward with site A and do what's called a site qualification visitor, an SQV. And that's when they send the CRO and or the sponsor, send personnel out to your site to review your site, make sure that it lives up to the capabilities that you said that you have. Talk to your staff, talk to not only staff being the study support team staff, such as the feasibility contracting and regulatory specialists, but also they'll want to talk to your clinical research coordinators, which are the research nurses is how I think of them. They help you, they're like your medical assistant in research and they help you run the trial and document all the data and submit all the data. So they'll want to come in, do their interviews, put their own eyes on your site, look at what equipment you have, make sure, look at your, even your, sometimes they'll look at your SOPs and just make sure that your site is qualified to run the trial. That's the SQV, just an ensuring qualification. And that is mandated by the FDA for these sponsors and CROs. So after that, they'll go back to their headquarters, they'll all talk and if they decide that your site would be successful in running the trial in their viewpoint, you will receive an email saying that you are either awarded or not awarded the trial. Let's say that you are awarded the trial for the purpose of this talk. At that point, what will start is a contract negotiation because you won't want to run a trial without having a contract in place dictating what, you know, what you will be paid per subject, per visit and other aspects of running the trial that will dictate what their responsibilities are and your responsibilities apart from what the FDA says the responsibilities are from the, from the site and the, and the sponsor. There may be some other responsibilities outlined in the contract. So that will come to you as, as a initial contract. There will be a lot of markup that happens at that point as we negotiate cost and, and other terms. We, we have a attorney that we have on retainer and we send all of our contracts to an attorney who is well versed in research contracts. So, so she reviews all of those for us as well. And then again, it's, it's a process. It truly is a contract negotiation. Once that has been finalized, then in order to actually start running the trial, you need to have a site initiation visit in which again, this can be virtual, you know, post COVID we've been doing more and more virtual, but the study and or the sponsor will send people again out to your site and they will go through a slide deck that they have composed for the site initiation visit, just ensuring that we are aware of the inclusion and exclusion criteria, what the requirement, the laboratory requirements, the PK requirements, they just go over the highlights of the protocol to make sure that we are all on the same page. All of our questions are answered. And all the regulatory aspects of running the trial are performed as well in regards to making sure I have oversight and training. I being the PI has oversight and training of all the personnel and ensuring that, that that has been documented appropriately. So as you can see, there's lots of, of different aspects there. In addition, they'll want any training that needs study specific training that needs to be done by the principal investigator and or the sub investigator investigator to be performed before you get what's called the green light. You get an email saying, okay, you are ready to start enrolling for the trial. You have achieved all of the requirements. You have checked all the boxes and you are now ready to start running the trial. So many, many steps are involved. You can see I listed the majority of them here, but even under each one, there's many other steps involved. So it can be daunting to get a start a trial up and running and especially your first one. But I think if you have a experienced clinical research coordinator and or someone who has done some of this study support work like, like this, even, even just one person can help you very much as you as you work through the process and then reach out to your peers as well who are in research and they can be helpful as you have questions. So, as I mentioned, there's a few different members of a study support site support team, and these are reflecting my team and certainly other, other research clinics may have very different roles and responsibilities. But for me, the feasibility specialist is someone who receives all the feasibility questionnaires. And these questionnaires can become, can come before, even after they've been awarded the study in terms of, are you willing to do a long-term extension, right? Which can be a whole separate study in addition to the initial pivotal trial. And again, the idea is to gauge the site's interesting capabilities. As I mentioned, PI experience is a big one. Although if you've never run a trial in a certain condition, that doesn't mean that you'll be excluded because they've reached out to you for a reason. So you want to be honest about your experience. You want to be honest about your competing trials. And then, as I mentioned, your database is going to be the easiest way, a database of patients is going to be the easiest way for you to recruit for any trial. And so they'll want to know how many patients you have with the condition that they are, that they, that they are focusing on and how many may meet the inclusion exclusion criteria based at, you know, from your database. And that, that can be really difficult to answer because, you know, we don't have such great ability to drill down into the, to the true details of every one of our patients in terms of, you know, how many patients are on a biologic or, or have completed a bio or have been on the biologic in the last six months. It's really difficult to get down to that level of detail on, on a database search, but you do the best you can and you give them kind of estimates based on your expertise. In addition to a feasibility specialist, there's the contracting specialist, right? So the feasibility specialist is really focused on that initial phase, kind of getting to a site qualification visit, and then it kind of is handed off to a contracting specialist where we receive the contract and that's when the negotiation happens. And actually this is probably one of the most important people because understanding what is fair for compensation for any of the activities in a trial, including study startup activities, what happens if you get audited by the FDA, if they are requiring you to scan and send many documents, all of these different activities you'll want in your contract with fees associated with it, because you'll want to ensure that you are covered so that you're not working for free afterwards. So it really takes a special person, a contracting specialist with experience to comb through the protocol, really understand what the different procedures and activities will be at each visit so that we are charging for each one of those, but also making sure that we are charging for any eventuality so that, again, we aren't working for free. So that is the big focus of the contracting specialist. And the other thing is to consider subjects get stipends for their time and effort. And depending on where you live, the stipend may need to be a little bit higher to compensate for that time and effort in a place where if you're in New York City, it's going to be much more expensive than if you are in Albuquerque. So negotiating the subject stipend is important as well to ensure that your subjects feel like they are being compensated appropriately for their time and effort. And that is really just a pass through in a contract, but you'll want to make sure that you do that with a good thought process and some intention behind it. Then there's the regulatory specialist. So these are, as you can imagine, there's multiple different submissions that need to go to the Institutional Review Board, the IRB, which ensures that the protocol is fair and that you are ethically treating subjects and everything you're doing is for the best of the subject. And so you have to submit regulatory submissions. You have to make sure that there's good communication between the IRB and the sponsor and your site as well. And then as regulatory queries come up and consent form submissions come up, you have somebody that can help you with the questions that may come up from the IRB, from the sponsor. Make sure that as you get adverse events that are reporting, especially serious adverse events, those are submitted appropriately to the IRB and the sponsor. All of the things that are in the back office-type work, because we're working with human subjects and this is tightly regulated by the governmental agency, there are multiple regulations involved and you need to have someone that is overseeing all that regulatory in order to not run afoul of the law. Because honestly, this is a legal contract that you sign. There's a Form 1572 that an investigator signs with the FDA. And if there is untoward activity and it can be perceived as being a violation of the contract and illegal, and it could even result in jail time. So you'll want to make sure that everything you do is above board and that you are complying with all regulations and submitting all the appropriate paperwork to show that. Okay. Now I think we need to talk about standing operating procedures because this is truly like the Bible of your site. Standard operating procedures are detailed written instructions to achieve uniformity of the performance of a specific function. And that's from the ICH, the GCP, the Good Clinical Practice Handbook, which is again, another Bible of research. And so you need to make sure that you have standard operating procedures for nearly everything that you do, because those will inform kind of why and how you are doing it. And should you get audited, you can refer to your SOPs if there are any questions. So we are trying to ensure compliance with good clinical practice with the IRB and the FDA, consistency between personnel trials and locations. If you have multiple locations, that ensures consistency of data collection and essentially consistency of competency. And then efficiency, because you would be using in an SOP a method that has been vigorously examined and is something that has stood the test of time. And so it makes sense to do it that way that is outlined in the SOP. So remember the regulatory requirements for SOPs, as I mentioned, adequate supervision of the conduct of the trial is in the FDA guidance, our investigator responsibilities. And so the investigator should develop a plan for supervision and oversight at the site. A plan might include the following SOPs. So the FDA is even giving us an idea of what we need to include. Correction and documentation of problems, documenting, reviewing the performance of delegated tasks. So I delegate, the principal investigator delegates tasks to the staff because all those tasks really do lie at the hands of the investigator who is ultimately responsible for running the trial. The consent process as well, that is a very important part of the running the trial is how you consent the patient to the trial and ensuring that you have a rigorous standard operating procedure that outlines how the consent is performed at your site. Ensuring that the source data, so source documents are what we put the native data into. So those are called source documents or electronic data capture, EDC documents as well, and making sure that they are accurate based on what we are capturing in the clinic office, in the clinic room, I should say, contemporaneous and original. You're not copying and you're not trying to do it after the fact. And then you're also probably most importantly ensuring the study staff comply with the protocol because everything is based on the protocol and adverse event assessment and reporting is also important as well. So all of that should be listed in a SOP. Other points to consider within an SOP, make sure that the author who writes them is familiar with the process. You don't want any person that you have in the clinic writing your SOPs. You want to make sure that this person has experience and understands what they're writing about. Keep it simple and question the necessity of each step. This is really a way to, it's an efficiency opportunity to really make sure that what you're doing is important. Involve as few people as possible to cut down on the number of mistakes, test and verify each step. And the other thing is, and this can be difficult as regular review and revision, which can be difficult, right? Because you write your SOPs and kind of forget about them as you just, they become commonplace for you, you refer to them, but they need to be reviewed annually and you need to sign off on that review as well as any revisions that need to be performed in order to comply with ever-changing FDA guidelines. In terms of if you do get an FDA audit, the process description inspectors assess whether the organization has cohesively documented all good clinical practice relevant activities. You want to make sure that the SOPs are readily available to personnel and accessible and in relevant areas where tasks are performed. So we recently had an FDA inspection and we had to make sure the first thing they wanted to look at was our SOPs and then use those to inform them of how we perform the trial. So I have firsthand knowledge of how SOPs are important. And then again, the adherence to the SOPs, ensuring that documented procedures are being executed as specified in the SOPs. So I think I'm really just kind of focusing in on how important it is to have SOPs that reflect what you do as you run the trial. They should include references, commonly used references include the following. You can see the Code of Federal Regulations is mentioned there in multiple ways, the good clinical practice as well, and then the common rule also. And that's outside the scope of this talk, but essentially just make sure that as you write through your SOPs, you do reference back to codes and regulations so that there is a basis for the SOP itself. So if you're looking at a template of an SOP, you want to make sure you have a title, a purpose of the SOP, policy statements and definitions. If you're referring to Code of Federal Regulations, for example, how you're going to complete the process, which version number and the effective date, your signature and date, authorized signature and date as well, if you are not the same author, as the authorizer and any references as I mentioned previously. Okay, well, thank you very much. That's just an overview of how we get started with clinical trials in terms of the people involved, the process involved. I wanted to focus on SOPs so that you understand how important those are and give you an idea of how to start developing your own SOPs as well. There are opportunities to use outside resources to help you write the SOPs, but the other thing to remember is to constantly review them so they're contemporaneous with your practice as well as with the updated regulations. Thank you very much.

clinical trials

dermatology

SOPs

FDA audits

contract negotiations

regulatory compliance