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Module_1_Griffiths_rev5

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Hello, I'm Prof. Chris Griffiths, from the University of Manchester and today I'm going to talk about the importance of Real World Evidence in the management of psoriasis, in particular relevance to clinical trials and the differences between that and real world. I have some disclosures, which you can see here in front of you, I've worked with a number of different companies over the years, particularly around psoriasis and new treatments for the disease. The contents of this program are divided into 4 modules: the first is an introduction to Real World Evidence, the second is around the registry that we run in the UK, the BADBIR, module 3 is about other registries in psoriasis around the world and module 4 is on some work that we're running from Manchester in collaboration with the World Health Organization, called the Global Psoriasis Atlas. I'll begin with Real World Evidence and introduce you to that concept. So, what is Real World Evidence? Well, there's a couple of definitions. The first is by ISPOR, which is the International Society for Pharmacoeconomics and Outcomes Research, which talks about retrospective/ prospective observational studies, registries and pragmatic clinical trials with real-world elements, so it's a constellation of different data sources. And then the Food and Drug Administration, the FDA in the USA, talk about their Real-World Evidence Program, which again includes electronic health records, claims and billing data, from private providers for healthcare, registries and then, increasingly nowadays, data from personal devices and health applications. The number of different sources of real-world data I've alluded to: the patient chart reviews and electronic health records which are becoming increasingly used in hospitals, not just in Europe, but of course across the world. Surveys of patients and healthcare practitioners and the general public, mobile health and wearable technologies, health claims databases, patient registries, which we'll analyse in detail in the 2nd and 3rd module and then non-interventional studies or observational studies, which are increasingly becoming part of the way we assess new medications for psoriasis and other diseases. The first question is: how does RWE differ from what probably most of you are used to, which is the evidence we see from Randomized Controlled Trials. Here, we've divided these into Randomized Controlled Trials, RCT versus RWE, which is the Real-World Evidence. RCT, the purpose is to look at efficacy, RWE is looking at effectiveness. The RCT, of course, is experimental, it's a contrived situation, RWE is real-world, of course. RCT are designed and there are fixed pattern of treatment, the dosing has to be fixed or equivalent throughout the study whilst the RWE is really as it happens in our clinical practice, so it's a variable pattern. RCT, the subjects are homogenous and they are selected according to eligibility criteria, RWE is taking all comers who would come to a regular clinic the attending physician of RCT is the investigator, whilst the RWE's is a number of different practitioners in a number of different clinical settings and then in RCT there's sometimes an active comparator or placebo and the patient monitoring is according to the protocol, whilst RWE there's lots of alternatives, there is no protocol and it's highly changeable. So there's a big difference between the two. Obviously, we're all beholden to regulatory authorities, so how do they view RWE? I've mentioned the FDA, Food and Drug Administration earlier on and they are looking to RWE to help support approval of new indications for approved drugs and also for post-approval study requirements, so they are aligned with RWE. In Europe, they are also supportive looking at the evidence lifecycle and how this evidence from the real world compliments the information we have from the very set criteria of a RCT. This plays a greater role in post-licensing and also in long term safety analysis. There's a discussion about on there should be consistency between RCTs and this is a study which I draw your attention to, published in the Journal of the American Academy of Dermatology a year ago where they looked at, in comparing studies eligible for inclusion from a variety of different sources, the usual sources we use for these searches, Medline, EMBASE and Cochrane Library, looking at a number of different biologic therapies we're familiar with, used for adults with moderate-to -severe chronic plaque psoriasis. Using statistical analysis, they provided estimates for probability of a PASI response and the relative risk between those, looking at the standardized outcomes of 50% improvement in baseline psoriasis severity takes the PASI 50 or PASI 75 or even PASI 90, which is a 90% improvement. And what they found was that they analysed over 1600 trials, 34 of them were included in their ultimate analysis, As you can see on the slide, 3 were adalimumab, 3 apremilast, 3 brodalumab etc, and the average duration of trials was 12 weeks, with a range of 10 to 16 weeks and the mean baseline PASI was 19 to 28, which is the criteria that we normally use, and psoriatic arthritis occurred in around about 25% of patients, the mean age we see in nearly all the studies is about 40/45 years of age. Many of them had previous biologics or previous systemic therapies, up to about a third of them had previous biologic therapies, so some of these patients were not biologic naïves. And then when they started compare the responses, you can see here a PASI 90, 90% improvement, which I think nowadays we should be looking for PASI 90 and 90% improvement for psoriasis as the key outcome measure moving on from the old fashioned PASI 75: I think we can now start to tell patients that we can aim for it being almost clear or, in some patients, clear. So we're raising the bar, which I think is fantastic, and you can see here in the way that this slide is constructed that Ixekizumab, on the left hand side of the slide, demonstrates a greater likelihood of achieving PASI 90, versus placebo, and if you move down, that is higher than Brodalumab, Infliximab, Secukinumab and then at the bottom there are Etanercept and Apremilast. This is intuitive, I guess, this is the way that most of us would think about these biologic therapies as the hierarchy of response; of course the response/ the outcome is not the whole story, but that gives you, in a nutshell, the differences between Ixekizumab, an anti-IL-17 biologic moving down through the other anti-IL-17s and Infliximab down to Etanercept and, of course, placebo. Some patients do actually have a response to placebo in clinical trials.

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Posted by: gabriella61 on Oct 23, 2019

Module_1_Griffiths_rev5

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