Okay, so the that, that sort of wraps up some general principles around things you need to watch out for when you're dealing with mid-study data changes, and there are many scenarios, there are many permutations of these sorts of things. But, but I think if you'll just kind of keep in mind the the sort of sanctity of the data that are collected. Being very, very careful to document any kind of versioning and changes that are going on, so that there are no surprises at the end of the study. And also, if you, if you'll keep in mind very carefully That you know, you've got data sets where you're adding or you're editing things in the middle of a study. for each individual element that changes, there's going to be this sort of before, and after that, that study change takes place, in terms of your data and how you might be able to analysis it. So, so don't take it lightly, do stress about it, it happens just, just deal with it. But make sure that you're getting your analysis team on board, make sure that you're doing. Full versioning, the full documentation, including in the SOPs if, if necessary. So, so we'll switch here and we'll talk about, another topic where, where there, there is this need to sort of think about, and, and maybe go in and review, data elements from, from your study. In the middle of a study and that, that really relates to reporting requirements. What I'll go over in the next several slides is, is, is really sort of a rule of thumb, for, for your particular study or for your particular trial you want to be careful and you want to make sure that you're, that you're plugged into the team that's that's devising the study or funding the study. And, and that you're, you're basically going away from the rule of thumb and, and getting real specific around the needs for your particular research study. However, as a general rule, we can sort of frame things out in, in an interim reporting domain, the way I'll presume out here. If you're doing a single site, one institution. clinical research study. This might be a, investigator initiated hypothesis-driven research study versus a phase 4 clinical trial where we're, where we're, collecting data and we'll be reporting it to the FDA. so we'll get to that one next. But you know, if we're doing that sort of single site clinical research study. At the very least, you'll be able to, You'll, you'll be required to, to go and and file progress reports for your sponsor. If it's a government sponsored study, you'll typically be doing those about once a year if you're in the U.S., and that's going to require sort of progress around a number of different domains. Including recruitment and sort of how things are going for the study. Any publications coming out of the study already. Just basically something for your funding agency. To, to, to understand it to know, that, that everything's going well. you'll also need, from a human subjects perspective, here in the U.S. it's the, it's the institutional review board, it's called other things at other, in other countries, and we've, we've touched on those briefly before. But you know any type of human subjects research, you're going to need a continuing review. Typically annually in the US, but sometimes with studies that are highly sensitive or that are deemed a little bit. a little bit more than, than average risk. You know, the might, require updates every six months or even three months but typically about once a year you'll need to report. most, most studies to the IRB as you get a continuing review approval to continue the study. this would include things like participant, participant enrollment both, you know, for the whole study duration time as well as this particular reporting period. these, these numbers could be used to detect over-recruitment. So if you've got permission from the IRB to study. 100 individuals in your, your enrollment numbers show that you've got 300 people that have been screened and enrolled in a study. The IRB in their roll as a human subject protection board. They're going to pay attention to that and that's going to be a huge red flag. On the other end of that spectrum, serious under-recruitment might trigger a stopping discussion. So you sort of have to consider the fact that if you have a study well-designed if it's a perfect study you're doing it very well. But you can't get enough patients going through that study to actually draw conclusive findings at the end. Maybe your power calculations say that you need a 100 patients to, to finish the study in order to have the statistical power. To prove one way or the other what you're looking to prove. If you've only got three patients over three years and it's a five year study, there's a pretty good indication that you're study, unless you do something completely drastic, is not going to be successful. And so that fourth, fifth, sixth individual that you recruit into your study. Worst case is they're actually putting themselves at some risk in reality and especially in the eyes of the IRB. They're putting themselves at some risk and you're putting them at some risk with really no. high probability at all, that the study is going to be completed. So there's no societal benefit and so, really serious, under-recruitment can trigger stop discussions. Course, with the IRB you're going to need to be reporting adverse events, anything that's happening to the patients that might be considered, attributable to the study procedures, data safety monitoring rules. Anytime there are, usually actually with IRB. I would consider adverse events, and there are grades to adverse events. Things that might go wrong that are attributable. You know, small ones might not need to be immediately reviewed but, but there is a threshold and the IRB will help you define that threshold. Where, when they happen you don't wait for that yearly review. You're going ahead and you're reporting those to the IRB immediately. Any kind of protocol violations, any kind of protocol modifications and they even. you know, in the US even key study personnel changes that those would, would, sort of trigger interim reporting requirements where we may need to use some of the data that you're, that we're collecting to report immediately to the IRB. So multi-center studies. These are similar to single studies. Single site studies. They might typically have data coordinating center operations reporting. So if you're coordinating, if you're the coordinating center for a particular study and you've got multiple sites there Then, your job as sort of interim reporting function of that study might be aggregate reporting across all of the sites. Maybe auditing quality, reporting. We're going to be covering those again in the next video sessions as well as maybe site assessment reports. So looking across all of the data and just looking site by site at how recruitment's going at each of those sites. If we're recruiting patients, are they staying for the duration of the study or are they dropping out. You know at a higher ratio at site A then site B,C and D and if so what do we need to do about that. Any kind of protocol deviations as we've mentioned earlier those are going to be things that need to be reported on not just at the single site level but looked at across the all of the sites conducting the study, and then finally data safety monitoring boards. So we covered the, you know, some of this information on the multicenter clinical research studies in, in the previous slide but, but going down about midway on this one I want to, want to point out that. In clinical trials the, these are cases where we might be, be looking at some sort of an intervention that, that that, that would sort of move on maybe into, into the FDA domain in terms of devices. Sort of proving the, the devices or new medication are Safe, tolerable and efficacious for for particular medical conditions. We usually call those clinical trials. For phase one, phase two trials, those are the small ones, sort of safety type trails. So typically those we're going to need IRB, maybe a data soft, safe. Safety monitoring plan which we'll talk about next and then in some cases we'll need a data safety monitoring board. In, in those, those cases would really be around high-risk and and possibly vulnerable populations. Phase three, the, the really, you know, once you get beyond sort of the smaller studies and you really get out there into the phase three, phase four type trials or multi-center clinical trials, then, you know, you're almost certain to need a data safety monitoring board. And we'll talk a little bit about what that is coming up. So, so real quick a couple of slides on, on data safety monitoring plans. And and basically the material that's left in this particular video segment we're really talking, or I'm really pulling a lot of information from some great websites from the National Institutes of Health. Those are referenced down at the bottom of the slides. this particular one, comes from the, National Institute on Drug Abuse. There's some great, great narrative text there on, why, what, and how to, how to approach this, this need for data safety monitoring plans for trials. and, and basically there's a lot of text here but just sort of highlighting the, what I think is the most relevant piece here. Each institute, or, or center, in, NIH should have a system for the appropriate oversight in monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity. Of the data for all NIH supported or conducted trials. I, I should say here that, if you're doing federal studies, if you're doing, studies that are sponsored by the government, you, you may not have a choice in this. I would also say, however, that, sometimes whether you're, whether it's a mandate or whether it's just the right thing to do. it's, it's worth taking a look at these concepts. And, even in, in sort of the investigator initiated stuff. If, if you feel, and particularly if your IRB feels, that, that there's greater than than, than, sort of average, or, or, ex, expected risk, they may require you to do a data safety monitoring plan anyways. It's one of those things that's, that's really a pretty good idea. So, ag, again, I won't go through it would sort of take a whole course in itself, going through data safety monitoring plans and boards. But I did just kind of pull out information about Things that need to go in an initial Data Safety Monitoring Plan. I won't, I won't stand here and read, you know, all of the text here. But I've kind of highlighted the, the, the text in maroon. Where, where, it might be interesting, or might be necessary, to sort of proactively sort of write those procedures, write the information down around how you're going to deal with adverse events and serious adverse events, and all of the things that you see here, There's also great information on that same website about, detailed plans and instructions for, for when you're actually conducting this study. So again, whether it's mandated to you or not, I would recommend that you really think hard about a data safety monitoring plan for your studies and trials. And then there's sort of this special case. So, so if a study is, is deemed, Large enough, if it's deemed of a certain magnitude where either the funding agency or the trial study team or even the IRB says, hey, this one actually goes beyond sort of a data safety monitoring plan. So, so that we can review that plan and the results coming back from that plan in these interim reports. We, we, we want to go a little bit further than that. We, we, we think that for this study and, and again the, the types of studies that we we described earlier. There needs to be an independent group of experts that, that are called together and they want these people to serve as a board. And we want them to meet frequently. Or, or, yeah. Regular intervals, con, concerning this particular study or trial. it may be a once a year. one that I'm familiar is, is, is last, sorry. the frequency is once every six months. these are experts that cannot be involved in the study. They can't have a conflict of interest. They really are an independent group of experts. And they serve as an advisory. in a, in an advisory role to come together you know, look at the, look at the accumulated study data. Look at it for safety, for, for conduct, for progress, and, and, and even efficacy. And, and they're job really is to make recommendations concerning the continuation, modification, or termination of the trial. What, what these independent reviewers feedback to, to the sponsor if, or to, to the study team through the sponsor really is is sort of a binding arrangement. So, so it's, it's not to be taken lightly in these data safety monitoring boards. That they're pulled together just so that you've got independent review, you've got some group that's not dependent on the funding for this particular study, and they have the ability and, and, and the responsibility to raise their hand and say, hey, this, this study is wrong. It, it should be changed, or it should be terminated. So, You know again, we've got, got a, a number of other things that the, items, that, that DSMB reviews on a regular basis, but, the DSMB should also assess the performance of study operations and any relevant issues as necessary. And, and then finally, the DSMB should conclude each review meeting. with, with recommendations. And, and those recommendations really must be complied with. for, for that study to continue and go on. So, the, these are all, you know? Just sort of a, sort of a shallow dive into talking about some pretty lengthy topics. But, you kn, you know? Even at that depth, you know? You could see that there's a lot of things that go on, once you start collecting data. Once you really start getting in the swing of things, you can unfortunately expect to encounter mid-study data change, needs. In almost every study. There are interim reporting requirements and particularly if you're getting into a. Into higher order phases and certainly trials. There's a lot that you need to think about in terms of creating and formulating and keeping up with data safety monitoring plans and boards. In the next segments we'll be looking at data quality and auditing.
