[MUSIC] Yeah, this section is going to go over some of the steps. We go through to plan for recruitments, we don't just open a trial. So what is the plan for recruitment and how do we make that plan? First we have to get an idea of how many patients are out there to be enrolled in the trial. And we can do that by looking at historic benchmarks from trials in our own experience and other people's experience. We can look at the practice patterns at different clinical sites. We need to estimate the conversion rate, how many people are we going to need to screen to enroll one patient. And, and some situations, we might even conduct a pilot study to see if a trial is feasible and to try to design the best plan for recruiting patients. So we need to have defined strategies that were continually refining throughout the trial and we're likely going to need multiple strategies. So in this slide, I've tried to provide an example of projections for recruitment in a trial. This follows a typical NIH format for planning a trial across the top you have the calendar years. So we're planning to complete this trial within five years, that's from soup to nuts from start up to finish. At least for NIH as they've become more focused on recruitment, you need to report each quarter, how recruitment is going, are you meeting your milestones? So you can see each year has 4/4. So you need to project how many people you will randomize overall in each quarter and what's the expectation for each site. So for this example, the initial planning period was for nine months. Typically a planning period might be 3-9 months for getting everything organized, getting the drug, getting it masked, getting the data system up all of those things, so it's a very busy period. So in this example, after nine months we are anticipating starting recruitment. Recruitment usually starts slowly as different clinical centers come online and open up for recruitment. And as everyone sort of gets in the groove and refines their strategy for finding participants. So in this example we start with sites recruiting one participant per quarter, gradually leading up to where they were able to recruit five participants per for years. The trial continues recruitment for three years until recruitment is ended in this example in October of 2026. With each site on average recruiting 52 participants, we need some time to follow the last participants enroll. So in this case there's a minimum of six months of follow up 2/4, and then finally once we completed the active part of recruiting and following participants. We need to close out the trial, ensure we have all the data, resolve any discrepancies in data and analyze the trials, so we need some time to do that. So this is an example of a five year plan for a clinical trial. Another thing that we should be doing in the planning phase for a clinical trial is what's called a SWOT analysis. So that's analyzing the strengths, weaknesses, opportunities and threats to your clinical trial. And I've provided an example from the literature that shows that kind of analysis for implementing trials in Ethiopia and Africa and they identify their strengths. Things like there's more enthusiasm for trials, they have an opportunity because there's been a huge expense of medical education in their countries. And they have large and diverse populations but there are weaknesses that they need to recognize and be prepared for like limited staffing or staff turnover. So that's one of the analyses that you should do before starting your trial, so that you can capitalize on your strengths and use them to help you deal with your weaknesses. Here's an example of a trial that I was involved in that is considered a pragmatic trial. The hypothesis was to compare a Zithromax fasten to re flumealas, to prevent all cause hospitalization or death in people with COPD. I selected this trial for an example because there was a lot of planning on how to embed this trial in clinical care and to enroll over 3000 participants. Some of that planning involved community engagement, this reflects back to what's your motivation for a trial. So, for this trial, there was a real clinical question. There had been clinical trials that showed that azithromycin was better than no treatment. And as well as other clinical trials of reforma last versus placebo, but there was no comparative data. So clinicians didn't know which treatment was better, and there was a real motivation to reduce rehospitalization rates among these patients. Because that had practical implications for Medicare reimbursement rates. So even though the results of this trial could have a large impact on what treatments were used to treat patients with COPD after they had an exacerbation. There was no anticipated regulatory impact, so who are the stakeholders? Of course, there are clinicians who have questions about what's the best treatment for their patients. The patients themselves, other stakeholders include other people and institutions that are directly impacted by which treatments are used for patients with COPD. Because it was very important to engage clinicians because we wanted to embed this trial in clinical care. We spent a lot of time developing tools to educate the positions about our question. Depicted on this slide is a poster we use to educate clinicians and the poster was designed with a lot of information. Much more information than you would try to give a patient. But the clinicians were an expert audience that we wanted to know the rationale behind the trial. So, we told them about the problem, we described the evidence about the two treatments that we were testing in the trial. What was the information known about their efficacy and side effects. And then finally, what was the actual question we were trying to answer in this trial. So that was one of the tools we used to engage clinicians, not patients, but of course patients are critical to clinical trials. And we have to think about what factors make people sign up for clinical trial. Their motivation can be access to new drugs that their health status is declining and they need new options. Many people join clinical trials because they want to contribute and help people who come after them have better treatments. They may want to learn more about their disease and how to treat it. And there may be monetary or financial incentives, such as being able to get drug without charge in some clinical trials or actual financial incentives. You also need to address their concerns about the risk of the treatments. What is the cost that they will incur in terms of money and time. And how will their privacy be protected and what physical discomforts might be encountered in the trial? We talked about design factors that influence recruitment, but there are operational factors as well. And some of these are how we advertise the strategy, how we advertise the trial, what is our media strategy? How do we plan to roll that out, site level factors like their own strategy and their capacity, and what is the budget for recruitment? Recruitment in a clinical trial really is a journey, we've spent a lot of time preparing for opening a trial. And so when we first get started, we're sort of crawling, we're want to go after the low hanging fruit. The people that maybe we've enrolled in other trials that are part of our practice. And then as we get up to speed, we can implement other strategies, reaching out to our colleagues, and using word of mouth. And finally we get to the point where in an all out push to meet our recruitment goals and to complete the trial. Typical strategies are to go after the low hanging fruit first. More proactive strategies sort of when we're walking is wearing electronic medical records to see what patients are in our systems that might be eligible. Many sites have registries of patients that have said that they are willing to be contacted for a trial. And a very successful strategy I've seen used at several sites is to actually have a group of recruiters for clinical trials. So they may recruit for several different types of trials, but that's what they're focused on contacting patients, and trying to get them to involve. There's different ways we can conduct outreach either with emails or letters using list, serves, presentations to other clinicians, to patient groups. And others and stakeholders media strategies, and also enlisting the help and support of influencers and trusted sources. So for example, patient advocacy groups like the COPD Foundation which was very much involved in our efforts to recruit for the reliance trial. The diagram that is depicting pathways to recruitment shown in this slide shows that there might be different pathways. If you were an outpatient or an inpatient and the things that need to be considered. Is there enough time in this particular situation to recruit a patient, or do we want to schedule a later visit for when both the patient and the staff have time? Are there the facilities to talk in private with the patients, and do you have access to the internet in this particular trial? Because often trials rely on the internet to enroll and randomize participants. So we provided a decision tree for sites to select what they think the best pathway for this particular patient is. So this slide depicts one pathway for enrollment into the reliance trial. You can see each step is outlined in the pathway, and we've even depicted which individuals are involved of course the patients always involved. But there may be a clinician involved who hands off to a coordinator and it shows what a complex process recruitment into a trial is. And that you really need to plan for it up front, this isn't something that just happens organically. So a lot of effort was put in up front in planning to try to embed this pragmatic trial in clinical practice. [MUSIC]
