Hello, and welcome to today's webcast, Successful Investigator-Initiated Studies in the ICU. My name is Komal Pandya, and I'm an associate professor at the University of Kentucky Medical Center in Lexington, Kentucky. I will be moderating today's webcast. A recording of this webcast will be available within five to seven business days. To access the recording, log into mysccm.org and navigate to the My Learning tab. A few housekeeping items before we get started. There will be a Q&A session at the end of the presentation. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce your speaker for today. John Devlin is a professor of pharmacy at Northeastern University, a critical care pharmacist and associate scientist in the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital, and instructor of medicine at Harvard Medical School in Boston, Massachusetts. His research focuses on the detection, prevention, and treatment of delirium and disrupted sleep in the ICU. Dr. Devlin chaired SCCM's 2018 PADIS guidelines and served as panel member for ATS's recent ICU Sleep Research Task Force. He currently serves as a NIDUS co-investigator, co-directing its dissemination core and annual research boot camp. He's also a member of the editorial boards of Critical Care Medicine and Pharmacotherapy and is a past president of the American Delirium Society. And now I'll turn things over to our presenter. Great. Thanks very much, Kamal. Welcome everybody. Really glad you're joining us today. The overall goal of this program today is ICU clinicians and researchers, I know you have many, many great ideas and foundations and both the device and pharmaceutical industry want your ideas. They depend on you to investigate their products. And so today, what we're really going to be focusing on is identifying strong research questions that will be interested to industry and foundations. We're going to talk about aspects of developing a high quality research proposal, although this will be sort of Research Methods 101 that will really help sell your project. And then assuming you get funding, which we hope you all will as you embark on a new project, some of the strategies and a lot of this is based on some of my own experiences, implementing a funded investigator initiated research study in the ICU clinical setting. What we're not going to be talking about today is NIH funding. So any federal award like PCORI, Department of Defense, or HRQ, we're really going to be sticking to foundations and industry. So we're going to start right off the top with the polling question, which study would industry be most interested in funding? A phase three trial to obtain a new indication, evaluating a new dosing strategy for a current indication, a case series to facilitate new formulary additions. So we'll give you a couple seconds here to pick one of these three. Okay, so this is interesting. Most people selected number, the first question, a new phase three trial to obtain a new indication. As we go through the program today, I'll be talking about why this probably won't be the case. Most device and pharmaceutical industry companies are really focused on keeping these studies in-house. The answer that I was really looking for, which I'm realizing I haven't given you any content yet, is evaluating a new dosing strategy for a current indication. Generally a case series to facilitate a new formulary addition. This to me is probably not rigorous research and there's some conflicts here potentially depending on the situation. An industry might ask you to do this, but it's probably not really a true investigator initiated study. So let's just talk about some of the industry considerations. Generally a company is going to focus on medication and devices already marketed in the United States. As I just alluded to, most phase two and phase three research is conducted in-house. It doesn't mean that they're doing the study in-house. They're certainly doing it potentially in your ICU, but this doesn't really fit the definition for an investigator initiated study. These are managed directly by the company. They're the sponsor. Whereas investigator initiated research, you're the sponsor of the study. Usually it would be done through a large CRO and many it's multi-site. Obviously this is kind of a no-brainer, but the industry is focused on expanding their market by selling more product. So really interested in exploratory studies focused on evaluating efficacy and safety potentially for a new indication, but not necessarily doing a phase three study to obtain that new indication. This helps a company decide whether conducting additional phase three trials should be conducted in conjunction with the FDA to seek a new product invitation. The results of published studies that are exempt from an investigational new drug application and evaluating products for indications outside of the product label can be impactful in boosting off-label product sales. And certainly in the ICU, there's a lot of off-label medication prescribing. They're also very, very interested in evaluating real life efficiency, particularly in populations that were excluded from phase three labeling studies. Even if these studies were conducted in the ICU, a lot of these phase three studies have very, very rigorous inclusion exclusion criteria. They're also interested in evaluating outcomes, not evaluating phase three labeling trials for both safety and efficacy. And sometimes there's outcomes that the FDA might not have deemed important in a phase three study to evaluate. So the company's not going to do it, but sometimes these outcomes are very clinically important. And some of these could be longer term post-ICU outcomes as well. And then thinking about new administration or dosing strategies. For example, you know, many times a tablet might be administered in the ICU, but we can't the patient can't swallow. So they might be crushing it or reformulating the tablet, putting it down the feeding tube. So a simple bioavailability study, potentially maybe if the drug binds with or without enteral feeding when administered would be a type of investigator-initiated research. And then looking at economic outcomes and many other related outcomes that generally wouldn't be done in a phase three study are very important industry. So just a investigator-initiated studies are also called externally sponsored scientific research. And, you know, there's many different definitions, but it's research that is initiated and managed by an external researcher who assumes the legal and regulatory responsibility for the conduct and management of the research as defined by the applicable regulations and laws of the country. So in the United States, this would be primarily the FDA. This is just for one company's website, you know, our company supports interventional clinical research involving authorized, unauthorized, or discontinued products from our company. Observational research, such as the product of interventional or non-interventional research using data collected by observing clinical practice in our patient self-reports. And then certainly industries often focus as interested as well in translational research. So non-clinical research involving products of all diseases and phases of development, including in vitro, in vivo, and ex vivo biomedical research. So this is again from a large pharmaceutical company's website. Our company requires from the investigators requesting support, your proposal must be supported by preclinical or clinical data and have a strong rationale. We're going to talk about this. Must have the scientific, technical, and operational capabilities to conduct the study. You must submit an IND application if necessary. We'll talk about this too in terms of what's an IND-exempt study. She's very, very focused on, you know, that you could deliver the study, the results on time, and foundations are as well, whereas sometimes, you know, with the NIH, you can get no-cost extensions. It's a little easier to stretch things out, realizing there's always lots of barriers and studies take longer to enroll than initially anticipated. Companies are going to want a final report, which usually would be a publication. They want regular study status updates, and the company's not generally going to provide the analytic support, so you need to make sure that you have the statistical support available for the data analysis in-house or through other consulting services. What is the... This is again from the same company's website. What is the submission review process? Generally, this is all done online. The company accepts proposals via submission tool found on this page. Please follow the instructions to register a username and password. The non-company researcher should submit either a clinical proposal or a non-clinical protocol, and it's important to differentiate the proposals, so proposals are very short, focused protocols. They'll have a multidisciplinary team in-house of experts in the company on the medical side to review these, and usually, they're pretty quick with giving responses. Once a clinical proposal is approved, the non-company researcher will be invited to submit a full, much longer full research protocol. I think it's important to realize that it's important to have medical side engagement. Generally, the first point person that I would turn to would be a local medical science liaison. Invite them to meet, build a relationship with this person, talk to them, invite them to your institution, if you're allowed to, take them into your ICU. Talk about, first, try to ask questions about what the company's future priorities are with its drug or device. These might not be obvious to you as a clinician. Try to, this shouldn't happen, but sometimes it does, divert the discussion away from the current formulary status of the drug or device at your institution. In the first meeting, be careful about sharing all the details regarding your research ideas, realizing you'll have to put them into the initial proposal. It's important as well, if you're a junior researcher without a lot of clinical research or clinical trials experience, consider including a more senior colleague in these meetings. This would be someone that would be a mentor to you. Industry's very interested in first impressions, and they're going to report back, the medical science liaison, to their in-house team. If you're not a physician, so if you're a pharmacist or nurse or another non-physician, consider including a physician colleague in the meetings. The physician might not be the person who's leading the study. As a nurse or pharmacist, you might be, but it confers the company, will make sure there's access to patients. Some companies, and I've run into this as a pharmacist, will only allow principal investigators for the study, and this could be the case based on your research administration or IRB as well, and then confirm you correctly understand the company's IIR submission process. Ask about timelines. Start asking about money, because you're going to have to start thinking about the budget for your project, and it's not wrong to start asking about budget ranges, what are the ranges that they might generally fund for IIR submissions. Emphasize your team's experience in designing, completing, and publishing funded research. Highlight the research culture of your ICU. Even if you've published and completed research in other areas, companies are very interested in knowing that you could perform and that you have experience in recruiting, enrolling, and completing studies. Make sure that you could confirm you have adequately monthly patient volumes, if you're looking at a small subset of patients, again, confirming that you have access to your research population. This involves talking with attending physicians, obviously usually starting with the unit director, that they're going to be supportive of enrolling their patients in your study, so generally there's going to be, if they feel the study is important, there might be some equipoise on their part. Have you discussed how you're, if you're enrolling in a ICU that does a lot of other clinical research and there could be competing studies, make sure you talk to those PIs, and generally there's always great ways that you could work to enroll patients concomitantly and sort of share patients, or sometimes you can co-enroll depending on the intervention. Make sure that you have adequate protected research time. Clinical research can always happen on evenings and weekends if you're a busy clinician working Monday to Friday. Confirm that you have access to research assistants and coordinators for the study. They don't have to do all the work, but it's important, for example, to have a, you know, maybe a part-time regulars coordinator, someone that could really help set up your study database. Making sure that you're doing everything properly in terms of, you know, obtaining, documenting consent. There's just a lot of input that experienced researchers or research team members can help you, even if you don't need them to do all the work, because you might be consenting patients yourself. Confirm that you have adequate statistical support. And I would, this is just from my experience, I would try to avoid making the project's feasibility totally dependent on enrollment from multiple other centers. Now, this sometimes is critical for a larger study, but I would think about questions that you can start that are small or that you can answer just with your own institution. There's a lot of complexities with rolling out an investigator-initiated study to multiple other institutions, particularly if it's a randomized, you know, interventional study. And so it doesn't mean you can't do it, but you have to be aware of these complexities and really have good mentorship and relationships with the people at other centers that might be part of your study. So the foundations are a little bit different than the industry, right? So the foundations are much more focused on a specific patient population or a disease state and not as much focused on a specific drug or device. So they might be interested in, you know, ICU, they might be interested in older adults, they might be interested in ARDS, sepsis, et cetera. It's really important to, you know, know what are the goals of the foundation when they're going to have a call for research, investigator-initiated research submissions. Often there's mismatch between what you think they want and what they want. And that could, you know, that could certainly be a large barrier to success of them successfully considering your application. So what is the foundation's focus? You could obviously the website's a really, really good source, but you could talk to program officers there to find out what research project has the foundation funded in the past. You know, try to find out the names of these members of these people that have been funded and reach out to them, see if you could hop on a Zoom call or have a quick conversation with them. Sometimes they might even share with you their application. You know, some foundations put a much greater priority on early stage investigators, which is great. So that's where that mentorship process works. And you might score much greater if you're a junior investigator, obviously working under mentorship and with a team. And then what's the submission process? What's the review process and what's the timeline? It's important to meet with someone in research administration at your institution who has experience working with the foundation. This could be within your department or it could be in, you know, a larger like Department of Medicine or Department of Surgery or even sort of at the institutional level, independent of a particular department. Research administration staff might have prior experience with the foundation you're targeting. Sometimes foundations as the investigator won't answer all your questions. Sometimes they prefer communication with institutional research administrators rather than just the PI. Remember, research administrators need to sign off on your protocol before it's submitted to a foundation. And discuss your proposal early with pre-award staff in your department or institution. Obviously, everybody has limits, five or 10-day limits before you submit things, but you want to be starting way before that as you start to flesh out your proposal. You know, if your target foundation is affiliated with a professional organization, for example, SCCM, I would probably consider becoming a member of the organization before submitting your proposal to show that at least you have some engagement with that organization. Consider engaging ICU patients and families in your proposal. Of course, this is critical with PCORI, but many foundations are patient and family-driven, and it's just good science to think about how you can formally evolve. There's lots of great examples out there. Many foundations first ask for a two- to three-page letter of intent to be submitted and reviewed, just like with industry, where you might submit a brief proposal before inviting investigators to submit a full research proposal. Do not underestimate the work required to develop a high-quality LOI. The LOI still has to really be clear on, you know, your background, your science, your intervention, your population, and all the basic steps in your study approach and analytic. It's just smaller. It's just shorter. It's usually only three pages, and, you know, you can't change a lot. If you get asked to submit a full application, you know, you can make some changes, but you have to really be careful not to submit a proposal that's, you know, quite a bit different than what you submitted as the LOI that was approved. So let's just spend a couple minutes talking about research question identification. I think this is most important for more junior investigators. Obviously, you know, most of this is common sense, I think. Carefully review the literature. You know, what are your clinical experience with yourself and your colleagues with the drug or the device? What have you talked about on rounds? You know, there's lots of information here. Discussions with colleagues at other institutions that might have more expertise or might be more specialized. Certainly professional meetings, both formal and informal discussions. Review abstracts presented at relevant meetings. You definitely want to go, you know, look at, you know, clinicaltrials.gov to see what other studies are currently ongoing with a device or a product or a disease state. And then review NIH reporters as well. That's where you're going to find all the NIH federally funded things. And again, as we talked about, continuous engagement with the company's medical side. They're going to give you some ideas. They're going to give you some ideas about what they're really looking for. So research question, creation and refinement. You know, make sure the research question is really interesting to you. If it's not, and, you know, you're going to be stuck with this question as a study for potentially two years as the principal investigator. So there's a lot of steps, you know, from writing the proposal, the protocol, implementing it, conducting the study and writing it up. So it has to be really important and interesting to you. You know, convert the research question obviously into a PICO question, an actionable PICO question that includes the patient population, intervention, comparison and outcome. Think about, you know, your question too. It's important not, you might initially think, I want to do the definitive study, but break it down. There's a number of initial steps that are really important research questions that you can consider that are perfect for foundation and industry-related studies that might not be the definitive randomized, multi-set of randomized controlled studies. Okay. It's important to identify what is your primary outcome. This is, you know, this drives a lot of your proposal. And certainly the sample size power analysis will be developed based on the primary outcome. And sometimes it takes a while to really figure out what is the primary outcome you should be using. You want something that's relevant to all the stakeholders in the study, which could be your funders, certainly patients and families, clinicians, and then maybe to insurance companies or hospital administrators. Obviously, secondary outcomes should be focused on secondary outcomes. And think about, companies and foundations are often, while you're enrolling a patient in a study, there could be some really interesting exploratory objectives that might be related to mechanistic questions. So maybe you're going to draw a biome, one or two, you know, vials of blood as a biomarker that you'll freeze and analyze later when you have some additional funding. But think about this in your proposal. It strengthens your proposal and it really helps show you're really thinking about all aspects of the questions you're developing. I would recommend developing a one-page draft research plan to share with the other research team members at your institution. So just a really brief background rationale, your primary objective, population intervention, and then just the bare highlights of the analytic approach for primary outcome. This can easily be, you know, sent around by email, set up a Zoom meeting with mentors, or face-to-face is even more preferable, and talk about revising this. This is before you would even develop, see a three or four-page initial proposal or an LOI to a foundation. I think it's important also to think about pilot feasibility studies, okay? It's really important to realize that a really, really small, underpowered, randomized controlled study is not really a pilot or feasibility studies. People will use that, but people are getting a little smarter, both at companies and foundations, and certainly at editors or journals. And you really want to make sure, if you're going to evaluate an outcome, that you have adequate sample and power to evaluate that outcome. But pilot feasibility studies are really, really important if you're looking at a new device or a new medication, potentially in a new population or a population subgroup. It can help you identify the most appropriate outcome measure. It looks at feasibility of recruitment and consent approach. Evaluation of acceptability adherence to the study intervention by both the patients and clinicians. Testing of data collection forms or questionnaires. Obviously, some of this depends on what your project is focused on. Evaluation of robustness of randomization procedures. Can you actually blind your intervention if that's important? Define study retention rates. And then it really establishes the completeness of your ability to collect data. These are all really, really important steps. And this could be a great project that the company might be very, very interested in, as well as foundations, before you start. And this would inform your next study that would be a larger randomized study. I think a pilot feasibility study is not an efficacy or effectiveness study. It's not an accepted method, actually, to determine the sample size for a larger trial. It's not really a proof of concept study. It's not really going to tell you whether an intervention, a drug, or a device is biologically active or inactive. And phase one or phase two studies, it doesn't replace those, where you might have surrogate markers. It's, again, it's all the steps to make sure you could do a larger, properly powered study. Okay. That said, it is important to be thinking about some preliminary data. First of all, look at your patient database, a database of your patient. Think about the confounders that should be considered, either for study inclusion or covariance, if you're going to do some post hoc adjustment. Make sure you have an adequate patient population to complete the study within the stated timeline, realizing if you have 100 patients available over a one year period, you're probably going to enroll no more than 50, maybe 40 to 50% of those, and then people will say no to consent. So you might end up with 20 to 30 of those 100 patients. Be really conservative. It's hard to get people enrolled and completed in any study. Do some surveys of your clinicians. Do some surveys of your patients and families. What is the clinician acceptance of the study intervention, the procedures, and then their potential roles in the study? And then determine the patient and family acceptance of study interventions and procedures. Important to be looking for study reviews, meta-analysis of the current literature. Is there a validation of a new evaluation? Do you need to validate a new evaluation method or laboratory analysis for your primary outcome? What's the feasibility intervention? Efficacy of the intervention. You want to show that it's probably going to work, even if it's just a case series of patient or it might be a small before after group. And it doesn't necessarily have to be the primary outcome you're evaluating. Sample size calculation, I could give a whole presentation on this, but you want to, first of all, define what a clinically relevant difference is in your proposed primary outcome, the variability by which the outcome is reported in the defined study population. And then think about your analytical approach. Generally, if it's a randomized control study, you want to keep your analytic approach fairly simple. But if you're, and certainly adapt your analytic approach from other published studies, and certainly evolve a statistician in all aspects of protocol development, define their role in data analysis, subsequent research publications, and certainly in many cases, if you're doing a randomized study, you're going to meet, your IRB is going to require you to have a DSMB. So the statistician is going to be helping send reports to them as well. Certainly in this day and age, I think we're seeing much more complex analytic approaches, particularly if you're doing some kind of control cohort study or another type of controlled study other than a randomized control study. So it's important if someone with some expertise to talk about the pluses and minuses. Study budget. Most companies will donate drug products and devices. If a placebo-controlled design is being considered, ask the company if they have a supply of the placebo. Often they do, even if the drug's already been marketed, they often have two or three years supply. It's really great if you can get that because then you can do a placebo-controlled study. It's very important to sit down and think about what are the study procedures that you're going to do? How do they differ from routine clinical procedures? Research staff should not be, bedside clinicians should not be tasked with delivering complex interventions or conducting clinical assessments outside of their normal scope of work. Most research administrators are really going to be looking at that. Certainly if it's an investigational medication that's going to be delivered, that's certainly within the scope of the bedside nurse or if they're already checking and documenting blood pressure, heart rate, or level of sedation. But if you're doing a lot more, these are roles that you have to build in study staff to do that. We all know how busy our bedside nurses are and the whole ICU team is, and they can't manage your study for you. You need to be there. You need to hire people. You need to hire assistants. You just need to figure out how you can get this done. There's costs of the research staff to screen and enroll patients, deliver the study intervention, evaluate outcomes, collect the study data. You need to include and justify this in the study budget. If you don't do this, the company or the foundation, it raises eyebrows where they're thinking, has this investigator really thought through all of this? As I mentioned, your institution certainly might be hesitant to allow to sign off on this proposal before it's submitted. Make sure you have costs for study consultants, including statisticians. Generally, from most of the investigator-initiated studies I've been involved with, they don't generally support principal investigator or co-investigator time, unless they're working, unless it's a consultant or someone that's working as a sub-investigator or a member of the research staff, but maybe sub-companies or sub-foundations will, but that's not usually the aim. You can't support your salary. Include all the add-on costs, such as IRB review, use of the investigational drug pharmacy services. Include the appropriate institutional overhead rate. Hospitals or universities have different costs for different types of awards. Foundations often have limits on these costs. So again, your research administration, pre-award people are gonna be signing off on this. So it's important to sit down with them as you develop your budget. And then again, work with a clinical trials contract expert to finalize the budget. So don't do the budget at the end. Start, the budget kind of informs you as you go through developing your whole proposal. Okay, so in the last few minutes, I'm gonna talk about, let's say you've been successively funded by a foundation or by industry. So you are a co-investigator, the principal investigator. You're ready to start your study. There's a lot of important steps to go through once you get that sort of notice of funding from the company or from a foundation. Okay, and some of these things you can certainly do if you have a good feeling you're gonna be funded. You don't need to wait for all of this. You definitely want sort of scope of work documents for all study procedures. Define the source documents. Are these gonna be REDCap? Are they gonna be other paper forms? Generally, be careful if you're having research staff document stuff at the bedside or having the ICU team document some things, be careful about having like study laptops there for people to enter things in. Sometimes it's better just to have a piece of paper and a study binder posted to the wall where this documentation happens. And that's what would be source document. You know, you wanna develop and pilot your study database. So this certainly has to meet all IRB security requirements. You want it, you know, REDCap is probably the most common. You wanna minimize data entry errors. You wanna facilitate easy transfer of your database to a statistical program. So talk to your statistician. You want to develop study educational materials for all relevant ICU clinician groups. And we'll talk more about the educational aspects of getting a study up and running in your ICU. And then enroll a trial patient. So kind of once you've done everything, and I'm going to go through a few other steps that relate to other things. Enroll a trial patient to make sure all aspects of study enrollment, randomization, intervention, delivery, and data collection go smoothly. You don't have to give them the intervention, but it's amazing how many things come up and you don't think about it. And you could do a lot of, you know, reevaluation of procedures, et cetera. So when you actually have your first official patient, there's not problems with, you know, enrollment, delivery, or data collection. Okay, next polling question. What step is most important when obtaining IRB approval? So first choice, obtain answers to your questions from the IRB office, and this is before. So before submitting your proposal to the IRB, have an outside IRB review your protocol first, hoping you've heard your IRB stuff to work with. So maybe you could deal with an outside IRB. And work with the IRB to finalize the research contract. Which one do you think is most correct here? Absolutely, so everybody's on the same page here. You know, I can't emphasize enough, even when you're planning a study, to sit down with an IRB administrator and talk about what could set be required, you know, just some of the common things to help drive your IRB application. Most IRBs, certainly they might give you permission to use an outside IRB for your study. But you want your IRB to be aware of your study and give you permission to do this. So they might say, you know, this isn't a study that we would normally do. It's an investigative-initiated study. You could use an outside IRB. It depends on the institution. But don't decide this on your own. And then, generally the IRB is part of research administration, but you're gonna have a contract, you know, opposed to a pre-award group that's gonna work to finalize the research contract between your institution and the foundation or the company. Okay, the IRB, people get really, you know, sort of hung up on this. And, you know, the IRB is there, they're very fair, but it's all about communication and knowing the things that they want. And if you're not sure what they want, ask them. You know, rather than just sort of guessing and submitting consent forms that are improperly formatted, you know, there's a lot of things that most institutional IRBs want in terms of verbiage in the actual study protocol. It might not be things that the company wanted. So you often will have to take your approved study protocol and rework it and revise it so it meets all the criteria for your institutional IRB to approve it. So just the whole, I would, most companies, most IRBs are gonna want you to register your study at clinicaltrials.gov. Just do that. It takes a little while, but it's not that hard. And you need to have institutional sign-off to be able to, you know, for them to sign off on the clinicaltrials.gov submission. If you're using a device or a drug on an off-label basis, it's important that you submit an IND application or IDE application if it's a device to the FDA. I won't go through all the steps, but basically it's a 30-day rule and you're expecting them not to respond. And if they do respond, if they don't respond, then you're IND or IDE exempt. And that, so that means you have an exemption because you're not seeking a new indication and this allows the FDA to say that you're not. But the, your IRB's gonna wanna see, they wanna see photocopies, they wanna see that you went through these steps, okay? Obtain a current version of the investigational drug or device brochure from the company. Most IRBs are gonna want this, even if the drug's already approved. Obtain a current package insert. Most IRBs are really gonna go through the risks and side effects that are reported in the package insert and if you don't mention these in your protocol in your risks and benefits section, they're gonna raise a lot of concern. You're gonna wanna establish a data and safety monitoring board. Usually these are people in the field that have research experience. As a pharmacist, I've chaired DSMB, many DSMBs. So it's usually, but they have to be people outside your institution. We already talked about reformatting your research protocol. Develop and inform consent using your IRBs template unless, you know, there's gonna be some of these investigative studies though that meet the requirements for minimal risk studies, risk research. And these might not be studies where you could still conduct the study, draw the blood or do a survey and you might not need to get consent from the clinicians or the patients or their families. Obviously you need to complete an FDA form 1572. Make sure you know how to put together a study binder or regulatory binder. This is where experienced research coordinators can help you develop all these. These are all institutional requirements at most universities or hospitals. And then make sure all your study personnel are up to date with their IRB training. I mean, these are all pretty basic things. And then reach out to an IRB administrator to discuss your protocol. We already talked about this. If you are, if you have a drug, it's important as soon as you get a pretty close to final protocol to get in touch with someone from investigational drug pharmacy. You know, share your protocols and meet with them. Talk about your study. You know, are you gonna want IDS to do randomization? What's their role? What exactly, how are they gonna get the study drug? How are they gonna store it? How are they gonna prepare it? There's gonna be people at the company that can help with some of these things. What's the IDS hours that support study enrollment? Sometimes it takes a while to get SORIN or EPIC study sets, order sets written for medication. So start this early. And then think about, you know, reasonable timelines for these steps. Most busy, you know, research centers have a lot, IDS has multiple life studies. You're not the only one, no matter who you are. So you need to really allow time for all of this to go through. And have that dialogue and just provide them with whatever you need to do. If you're gonna be using a device, I don't have as much expertise in this, but I do know if there's a device that's not already approved and doesn't have a sticker from your biomedical engineering group, you need to have that device approved so it can be plugged in and used in the ICU, even if it's only being used for research purposes. You can't just take a device, plug it in without going through biomedical engineering. Okay, research contracting. This is often the delay, delays the start of the enrollment. And this is where probably there's a lot of questions with the budget. As soon as you obtain studying award notifications, start the process. And, you know, it's important that these people are really, really busy. They have lots of other studies. So stay on top of them in a polite, sort of constructive way. Reach out to them with questions. Sometimes, you know, sometimes you're dealing with the, you know, they're often have a legal background. In many cases, you're dealing with lawyers in the company, and sometimes they go back and forth and back and forth. And you see these emails go back and forth, and it seems like they're going in circles. So there's certainly been cases where I've talked to my, you know, clinical trials office instead of a Zoom call with the people in the company, just to get over those last few steps where it seems like it's not working by email. And so there's, as a PI, you can't push, but you can certainly nudge the process along. So I see a clinician study education. You really want your clinicians to be aware of the study, exactly what their role is, and you want them to be supportive of the study. And so this all gets down into workload, and then also really making sure you're explaining to them the science and why your study's really important and why it's gonna help, you know, improve the care of critically ill adults or children at your institution and that of others. I think the first step before you even submit the study proposal or protocol to a foundation or company, meet with your ICU leadership. You know, they need to know what you're planning to do. Do they support this? They might have a lot of questions. They might have questions on the clear roles of what the study team's doing versus the ICU bedside clinicians. It's better to get all of this done before you submit it rather than try to sort this out later when it's harder to make protocol changes. How many patients can be enrolled concomitantly? Sometimes IDS will have limitations on this, but certainly, you know, the nurse and physician managers or administrators at your institution might as well. Discuss the educational plan and provide them with the draft educational materials. For nursing education, you know, it's impossible to educate every nurse on an in-depth basis that works nights and days in an ICU. What I've always done is sort of created, where nurses are teaching other nurses, so defining nurse stakeholders. And this is where I, it's by invitation. So, you know, usually have a personal relationship with these nurses and find out who's interested in this. And ask them, would you be a trainer for the study? So they're gonna go undergo a much more detailed study education, and they're gonna be an educational resource to their colleagues. And then, of course, you're always gonna be doing just-in-time education when you actually enroll a patient. So there's kind of the pre-enrollment before you've enrolled a patient, and keep that up regularly. And then once a patient is enrolled, then you're obviously talking to the team, the bedside nurse, exactly what's gonna happen over the next shift. And it's important to do this regularly. There's nothing worse than enrolling a patient in the study or say, we're gonna enroll a patient in the study and all the nurses look at you like I've never heard of the study before. And that could really put up some barriers. You know, keep all the education and materials for the sort of the stakeholder education really brief and focused. And what I usually do is I have an index binder next to the bedside that has much more detailed education materials. Because sometimes there's things that, you know, aren't critical, but if this happened, go to here, look at this. And that's a really, you know, easy go-to thing. For physician education, you know, I've always presented my studies, usually I can get five or 10 minutes at an ICU attending administrator meeting, and then follow up with a one-page pocket handout. If you're at a teaching institution, make sure you're continuously educating house staff that are rotating on and off the ICU service where you're enrolling. And then certainly if there's roles for RTs, physiotherapists, certainly other pharmacists, you know, if pharmacists are involved that are clinical pharmacists, you want to educate all these people too. And have independent, you know, education materials for all of these people. So in summary, hopefully you got a little bit of this, and I think we'll turn to some question and answers. Thank you so much for your presentation. I'll get us started. So you mentioned, you know, a great overview of the steps to take in getting things going. I know that this might be quite variable, but what would you say are like an example timeline for a project, like a minimum consideration from consumption to getting the study underway? What's been your experience in terms of timeline? Yeah, I think maybe I'll step back too, Camille. I would say, you know, to get the proposal, you know, talk to your colleagues, get that one page research plan developed, show that there's interest on the medical side, and then, you know, submit that online, you know, it's usually three or four page proposal or an LOI to a, you know, to a foundation. That's going to be probably, could be months, not a year, but it's going to be at least three or four months. There's a lot of things you need to do ahead of time. There could be some pilot data you want to collect. There's all kinds of things you want to get in there. And so that's probably at least three to six months, I would say. It depends. It depends on the team and the focus of what, how novel and innovative what you're doing is. And then once you get the funding letter, it usually takes at least three months to enroll your first patient, just with the contracts, IRB, education, IDS. But the key thing is with all of this, I think I emphasize is that you're doing all these steps concomitantly. Like you're not going to start with the IRB, wait two months, and then say, oh, we got IRB, let's go to, let's start doing education. You're kind of doing all these things over three months concomitantly. It's a busy time. Great, thank you. As many opportunities as you've had to conduct research in this manner, would you say, you know, with your first such project, what were some barriers and challenges that you uniquely experienced? And how did you work to kind of overcome and identify how to work through them? Yeah, I think, you know, one of my studies, I certainly talked to the nurse director and the physician director. This was in a large medical ICU. So I had their support, but I probably didn't spend the time I should really talking. And sometimes everybody communicates different ways, whether it's a meeting you're talking about, or whether you know the people that are more ICU research-based, and just say, just grabbing them after rounds, or, you know, some way just for 10 minutes, hey, I got this idea going, can I talk to you? I have a couple of questions. And getting them, so it might be a bad time, and they're like, set up an appointment with my admin. But I think it's really important to talk about, get their support for the study as well. It's not like you need to get signed up from every single attending physician, but you know the key ones that can help drive, you know, the research practice and stuff. And I think the other big thing is underestimating the importance of pilot data, feasibility data, you know, preliminary data, just thinking, well, let's just go right to this big study. And that's a big, big mistake. Start really small, be rigorous, you know, show the steps of what, if you do this project first, this is gonna be really valuable to a foundation or to industry, because this will give you all the information to maybe do a much larger study, which could be multi-center, to really answer the questions. But all of this is very, very valuable data, and certainly publishable by doing some of these steps initially. It takes some time. And I think the other thing is getting people with research expertise, if you're a junior, helping you. Again, they don't have to become full-time research nurses for you, but figuring out the way that you can get mentorship in all aspects of how to, you know, put together a regulatory binder, how to properly consent. Can you do, you know, does it have to be face-to-face consent? Can you do some kind of e-consent? There's all kinds of steps, and they can be a little overwhelming and confusing if you're really junior, of what the institution requires, and they're ever-changing. So generally, there's other researchers that are willing, as long as you go to them with questions and a focus, and not, you know, they're clear that they're not managing your study for you. Excellent. Well, thank you so much, Dr. Devlin, for your presentation. Again, for the audience at large, this webcast is being recorded. The recording will be available to registered attendees within five to seven business days. Log in to mysccm.org, and navigate to the My Learning tab to access the recording. That concludes our presentation for today. Thank you.

Webcast

Research

Clinical Research Design

2024

Professional

Dr. Devlin

Dr. John Devlin

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clinical research

investigator-initiated studies

ICU

research questions

funding sources

research proposal

research proposals

IRB approval process

IRB approval

mentorship