1 00:00:02,040 --> 00:00:03,930 Okay, this is Dr. Bob Wilden. 2 00:00:03,930 --> 00:00:07,800 I am doing a quick demo 3 00:00:07,800 --> 00:00:12,800 on the Clinical Pharmacogenomics Implementation Consortium 4 00:00:13,680 --> 00:00:17,730 and their website, which is very useful 5 00:00:17,730 --> 00:00:22,500 for looking up information that is clinically useful 6 00:00:22,500 --> 00:00:26,280 with regard to pharmacogenetics, pharmacogenomics 7 00:00:26,280 --> 00:00:29,850 or as we say, drug gene interactions. 8 00:00:29,850 --> 00:00:34,850 So I'm going to stop my video and talk about the screen 9 00:00:35,760 --> 00:00:39,180 and basically walk you through the site 10 00:00:39,180 --> 00:00:41,613 and how to look things up as you need them. 11 00:00:43,710 --> 00:00:47,700 Okay, so we are sharing screens. 12 00:00:47,700 --> 00:00:51,240 So this is the homepage, 13 00:00:51,240 --> 00:00:55,860 which is at cpicpgx.org. 14 00:00:55,860 --> 00:00:57,213 Very simple to remember. 15 00:00:58,140 --> 00:00:59,910 CPIC is the Clinical Pharmacogenomics, 16 00:00:59,910 --> 00:01:04,020 Implementation Consortium, and you can read more 17 00:01:04,020 --> 00:01:05,400 about the organization there. 18 00:01:05,400 --> 00:01:09,210 Basically they're here to provide guidelines 19 00:01:09,210 --> 00:01:13,140 and evidence assessments on drug gene interactions 20 00:01:13,140 --> 00:01:18,140 and their usability and recommendations 21 00:01:18,270 --> 00:01:20,980 for use once you have the genomic information 22 00:01:21,900 --> 00:01:24,600 in clinical prescribing. 23 00:01:24,600 --> 00:01:29,600 So there are several rubrics along the heading here, 24 00:01:31,260 --> 00:01:33,810 and I'm gonna click on into guidelines. 25 00:01:33,810 --> 00:01:36,330 So the guidelines are designed as it says, 26 00:01:36,330 --> 00:01:37,500 to help clinicians understand, 27 00:01:37,500 --> 00:01:41,850 how test results should be used to optimize drug therapy. 28 00:01:41,850 --> 00:01:43,500 They're not designed 29 00:01:43,500 --> 00:01:46,620 to tell you whether a test should be ordered. 30 00:01:46,620 --> 00:01:50,040 So there's a significant gap there. 31 00:01:50,040 --> 00:01:51,990 So you have to understand this as 32 00:01:51,990 --> 00:01:54,030 if you have the information, 33 00:01:54,030 --> 00:01:57,810 this isn't how you may wanna use it. 34 00:01:57,810 --> 00:01:59,820 If you don't have the information yet 35 00:01:59,820 --> 00:02:00,990 and you're trying to decide whether 36 00:02:00,990 --> 00:02:05,550 or not to do the test, CPIC is not about that. 37 00:02:05,550 --> 00:02:09,452 All right, so guidelines are here. 38 00:02:09,452 --> 00:02:13,350 They're all published in peer-reviewed journals 39 00:02:13,350 --> 00:02:16,200 and there are links within this to find them. 40 00:02:16,200 --> 00:02:20,670 So there is a search box here, 41 00:02:20,670 --> 00:02:22,880 so I'm gonna put in clopidogrel 42 00:02:27,480 --> 00:02:32,480 and very quickly, CYP2C19 and clopidogrel pop up. 43 00:02:33,660 --> 00:02:35,220 And so I'm gonna click on that 44 00:02:35,220 --> 00:02:39,420 and I get a webpage that gives the guidelines. 45 00:02:39,420 --> 00:02:44,130 It has a link to a PDF of the published paper 46 00:02:44,130 --> 00:02:48,000 which goes over the guidelines as published in 2013. 47 00:02:50,280 --> 00:02:54,330 And there's the next line is, updates since the publication. 48 00:02:54,330 --> 00:02:59,330 So in March 2017, it gives an update on what happened 49 00:02:59,520 --> 00:03:04,520 at the FDA and tells that the FDA level didn't change 50 00:03:05,250 --> 00:03:07,650 and the recommendations don't change. 51 00:03:07,650 --> 00:03:12,300 So there are really no changes to the recommendations. 52 00:03:12,300 --> 00:03:13,320 There are tables 53 00:03:13,320 --> 00:03:17,280 and figures in the main manuscript which are listed here. 54 00:03:17,280 --> 00:03:19,170 These tables in the manuscript are actually, 55 00:03:19,170 --> 00:03:21,060 really quite good. 56 00:03:21,060 --> 00:03:25,500 And if you wanna sort of jump ahead in your process, 57 00:03:25,500 --> 00:03:30,450 if you're in a hurry, you can open these manuscripts 58 00:03:30,450 --> 00:03:32,730 and jump to the tables 59 00:03:32,730 --> 00:03:35,460 and get a pretty clear picture of what you need 60 00:03:35,460 --> 00:03:37,833 to do in a particular situation quite quickly. 61 00:03:39,150 --> 00:03:41,190 There's a supplement here 62 00:03:41,190 --> 00:03:44,940 which has additional information that's linked. 63 00:03:44,940 --> 00:03:47,520 The tables and figures are listed in this table 64 00:03:47,520 --> 00:03:49,413 below from the supplement, 65 00:03:50,820 --> 00:03:54,540 and they include allele definition tables 66 00:03:54,540 --> 00:03:57,330 which most people don't have to deal with, 67 00:03:57,330 --> 00:04:00,570 allele functionality table, allele frequency table. 68 00:04:00,570 --> 00:04:02,190 These are things that are useful for people 69 00:04:02,190 --> 00:04:03,750 who are designing tests 70 00:04:03,750 --> 00:04:06,213 and trying to apply them to populations. 71 00:04:09,900 --> 00:04:14,040 But this is where one generates the information 72 00:04:14,040 --> 00:04:16,230 that comes out of a genotyping test 73 00:04:16,230 --> 00:04:21,040 and translates that step by step into a recommendation 74 00:04:22,530 --> 00:04:25,170 into a metabolizer status 75 00:04:25,170 --> 00:04:29,970 and into a recommendation for prescribing. 76 00:04:29,970 --> 00:04:33,480 So there additional links down here 77 00:04:33,480 --> 00:04:36,270 that you may be interested in, but basically the bulk 78 00:04:36,270 --> 00:04:38,310 of what clinicians are gonna be interested in is up here 79 00:04:38,310 --> 00:04:41,550 at the very top, this paper 80 00:04:41,550 --> 00:04:46,550 and potentially the linking into the tables, all right? 81 00:04:46,800 --> 00:04:48,430 So I'm gonna just open this 82 00:04:49,320 --> 00:04:54,320 and I'm gonna make sure that I am sharing that as well. 83 00:04:59,460 --> 00:05:04,460 Okay, and so here's the paper as it looks. 84 00:05:05,010 --> 00:05:06,660 The CPIC update 85 00:05:06,660 --> 00:05:11,660 and it gives information about it, gives background, 86 00:05:12,180 --> 00:05:15,060 gives genotype phenotypes. 87 00:05:15,060 --> 00:05:17,670 So here's the phenotypes associated with the genotypes 88 00:05:17,670 --> 00:05:22,670 and examples of the diplo types that maybe you commonly see. 89 00:05:25,050 --> 00:05:26,790 And as I scroll down, 90 00:05:26,790 --> 00:05:29,400 then there's therapy recommendations based 91 00:05:29,400 --> 00:05:32,370 on the CYP2C 19 status when using clopidogrel 92 00:05:32,370 --> 00:05:36,060 for the acute coronary syndrome, PCI patients, 93 00:05:36,060 --> 00:05:38,490 which is the patient group 94 00:05:38,490 --> 00:05:43,490 for which the protocol guidelines have the most data 95 00:05:43,890 --> 00:05:47,283 to support using the pharmacogenomics in practice. 96 00:05:48,240 --> 00:05:53,240 So that gives you the strength of the recommendations 97 00:05:54,240 --> 00:05:58,450 and the therapeutic recommendations, given the genotypes 98 00:06:00,688 --> 00:06:03,873 and the phenotype of metabolizer status. 99 00:06:05,310 --> 00:06:09,360 All right so there's lots in these papers. 100 00:06:09,360 --> 00:06:14,360 This one has an algorithm for suggesting clinical actions. 101 00:06:14,490 --> 00:06:17,760 And these are really well written and worth digging into 102 00:06:17,760 --> 00:06:20,730 if you are gonna be using these drugs 103 00:06:20,730 --> 00:06:25,730 and the pharmacogenomic test data on a regular basis. 104 00:06:26,070 --> 00:06:28,170 Or even irregularly, you can come to here 105 00:06:28,170 --> 00:06:31,080 and find the information that you're really looking for. 106 00:06:31,080 --> 00:06:36,080 So again, going back, here are the guidelines. 107 00:06:40,710 --> 00:06:45,690 For this one, you get there by going to guidelines, 108 00:06:45,690 --> 00:06:49,800 put in your drug of choice or your gene of choice. 109 00:06:49,800 --> 00:06:52,157 And so for example, if I put in CYP219, 110 00:06:55,980 --> 00:07:00,960 I can see that there are actually multiple drugs 111 00:07:00,960 --> 00:07:05,960 or drug classes for which CYP2C19 has recommendation 112 00:07:06,150 --> 00:07:09,960 or has guidelines in in CPIC. 113 00:07:09,960 --> 00:07:13,833 So it's a very, very, you know, useful approach. 114 00:07:14,790 --> 00:07:16,410 Up here at the top on the menu, again, 115 00:07:16,410 --> 00:07:19,470 we're gonna look at the gene drug list. 116 00:07:19,470 --> 00:07:23,520 It's kind of similar but it's kind 117 00:07:23,520 --> 00:07:25,290 of a more feature rich list. 118 00:07:25,290 --> 00:07:26,940 So if you're only looking for the guideline, 119 00:07:26,940 --> 00:07:30,030 that first rubric is the place where you wanna go 120 00:07:30,030 --> 00:07:34,320 if you wanna get a little bit more rich information 121 00:07:34,320 --> 00:07:37,030 about it, so let's just stick with CYP2C19. 122 00:07:40,830 --> 00:07:44,580 And you don't even have to click enter, it just pops up, 123 00:07:44,580 --> 00:07:46,680 fills up the table and here, 124 00:07:46,680 --> 00:07:49,530 you have your different gene drug pairs. 125 00:07:49,530 --> 00:07:51,720 Again, a link to the guideline that takes you back 126 00:07:51,720 --> 00:07:53,850 to the same place we were before. 127 00:07:53,850 --> 00:07:58,110 There's a column for the CPIC level which is the level 128 00:07:58,110 --> 00:08:00,800 of the evidence and the level of strength 129 00:08:00,800 --> 00:08:04,350 and support for the guideline. 130 00:08:04,350 --> 00:08:06,210 So these are all level A, 131 00:08:06,210 --> 00:08:10,440 which means the CPIC organization feels strongly 132 00:08:10,440 --> 00:08:13,383 about the validity of those guidelines. 133 00:08:15,000 --> 00:08:16,590 And CPIC level B are ones 134 00:08:16,590 --> 00:08:18,090 that have a little bit less evidence 135 00:08:18,090 --> 00:08:19,590 or a little bit less strength. 136 00:08:21,000 --> 00:08:23,490 And some of those are labeled B, 137 00:08:23,490 --> 00:08:25,140 but don't yet have guidelines written 138 00:08:25,140 --> 00:08:27,390 because they haven't gotten around to it. 139 00:08:27,390 --> 00:08:30,990 For example, those are coming bit by bit. 140 00:08:30,990 --> 00:08:32,700 There's some down here with CPIC level C 141 00:08:32,700 --> 00:08:36,240 and the definitions of the levels are available 142 00:08:36,240 --> 00:08:39,510 in here on the second link. 143 00:08:39,510 --> 00:08:41,820 So here's CPIC levels for genes and drugs. 144 00:08:41,820 --> 00:08:44,820 So the definitions of A, B and C are in there. 145 00:08:44,820 --> 00:08:48,270 The next column is pharmGKB levels of evidence 146 00:08:48,270 --> 00:08:53,270 which starts with one A, two A, three, et cetera 147 00:08:54,510 --> 00:08:57,900 and it's a different kind of level of evidence thing. 148 00:08:57,900 --> 00:09:00,690 And you can go to pharmGKB, 149 00:09:00,690 --> 00:09:03,139 which is linked in here somewhere, 150 00:09:03,139 --> 00:09:08,010 to get a better picture of what those levels 151 00:09:08,010 --> 00:09:08,843 of evidence are. 152 00:09:08,843 --> 00:09:11,220 Those are basically more the level 153 00:09:11,220 --> 00:09:15,720 of evidence relating to the analytical validity 154 00:09:15,720 --> 00:09:19,620 and the clinical validity, not the clinical utility 155 00:09:19,620 --> 00:09:23,193 of those particular drug gene pairs. 156 00:09:25,380 --> 00:09:29,070 PharmGKB also has all the background literature linked. 157 00:09:29,070 --> 00:09:31,230 So if you're really interested in one particular area, 158 00:09:31,230 --> 00:09:32,940 you can go to pharmGKP 159 00:09:32,940 --> 00:09:37,080 and pull up all the literature that's known about that 160 00:09:37,080 --> 00:09:39,363 and that's very helpful. 161 00:09:40,980 --> 00:09:45,263 The next column is, what is the pharmacogenomic category 162 00:09:48,600 --> 00:09:52,560 when you look at an FDA label for that particular drug 163 00:09:52,560 --> 00:09:54,900 and that's on the FDA website. 164 00:09:54,900 --> 00:09:57,150 We're gonna talk about that a little bit too. 165 00:09:57,990 --> 00:10:01,830 So the FDA label has these kinds of things. 166 00:10:01,830 --> 00:10:06,180 There's actionable, informative, there are other labels 167 00:10:06,180 --> 00:10:07,680 as well which are not shown here 168 00:10:07,680 --> 00:10:10,620 which may be like a black box warning, 169 00:10:10,620 --> 00:10:11,453 something that's really, 170 00:10:11,453 --> 00:10:13,983 really important to pay attention to. 171 00:10:16,530 --> 00:10:20,223 So you can play around with this and add other other genes. 172 00:10:22,230 --> 00:10:27,230 G6PD has a guideline for rasburicase 173 00:10:27,450 --> 00:10:31,750 and for example, the FDA label says that testing is required 174 00:10:32,640 --> 00:10:36,660 before you give rasburicase because the risk is quite high. 175 00:10:36,660 --> 00:10:41,460 If you have V6PD deficiency, you will really wanna know 176 00:10:41,460 --> 00:10:43,263 that before you give rasburicase. 177 00:10:44,100 --> 00:10:47,793 All right, so those are other examples here. 178 00:10:49,050 --> 00:10:53,773 Okay, so there's additional things here. 179 00:10:54,900 --> 00:10:57,240 So if you're interested in looking at this 180 00:10:57,240 --> 00:10:58,710 from a geneticist level, 181 00:10:58,710 --> 00:11:01,410 you can look at the specific genetic variant. 182 00:11:01,410 --> 00:11:06,180 So this is a protein variant, this is a CD NA variant here. 183 00:11:06,180 --> 00:11:10,380 And you can look those up in the same search mechanism 184 00:11:10,380 --> 00:11:13,020 and see if there are guidelines 185 00:11:13,020 --> 00:11:15,630 for those individual variants. 186 00:11:15,630 --> 00:11:20,630 So these are the guidelines that refer to Ivacaftor, 187 00:11:20,910 --> 00:11:24,990 for example, for CFTR, okay? 188 00:11:24,990 --> 00:11:28,320 So that's a really nice way 189 00:11:28,320 --> 00:11:30,810 to look at it in even a more different way. 190 00:11:30,810 --> 00:11:34,660 There's a big list of publications here 191 00:11:35,640 --> 00:11:38,790 that you can dig through. 192 00:11:38,790 --> 00:11:42,090 CPIC has meetings if you are a pharmacist, pharmacologist 193 00:11:42,090 --> 00:11:44,370 and somebody who knows a lot about this who wants 194 00:11:44,370 --> 00:11:47,100 to participate in CPIC, you can join in meetings, 195 00:11:47,100 --> 00:11:49,350 additional resources, working groups members 196 00:11:49,350 --> 00:11:52,080 and contact for the organization. 197 00:11:52,080 --> 00:11:55,230 But really, you know, the meat of what we wanted 198 00:11:55,230 --> 00:11:56,660 to talk about for the purposes 199 00:11:56,660 --> 00:12:00,150 of this little walkthrough is the guidelines 200 00:12:00,150 --> 00:12:04,320 and the genes and drugs and alleles, things. 201 00:12:04,320 --> 00:12:06,720 Thanks for listening to that. 202 00:12:06,720 --> 00:12:10,097 I will now go to the fda.gov 203 00:12:15,630 --> 00:12:20,630 and I'm gonna search for biomarkers table. 204 00:12:24,360 --> 00:12:26,270 And here's the table 205 00:12:26,270 --> 00:12:30,273 of pharmacogenomic biomarkers in drug labeling in the FDA. 206 00:12:31,920 --> 00:12:33,300 And I'm just gonna double check 207 00:12:33,300 --> 00:12:37,983 that we're still sharing the right bit here. 208 00:12:39,810 --> 00:12:42,663 Yep, we're on the main screen so we're good. 209 00:12:43,650 --> 00:12:48,390 And so this is an FDA US Food 210 00:12:48,390 --> 00:12:50,310 and Drug Administration website. 211 00:12:50,310 --> 00:12:54,990 So drugs which have biomarkers associated with them, 212 00:12:54,990 --> 00:12:59,730 that is measurements you can make on blood, 213 00:12:59,730 --> 00:13:04,730 DNA, urine, other things that help advise whether 214 00:13:06,660 --> 00:13:08,160 and how you should use that drug. 215 00:13:08,160 --> 00:13:09,900 That's a biomarker. 216 00:13:09,900 --> 00:13:14,900 And those biomarkers are part of the FDA approvals 217 00:13:15,360 --> 00:13:17,760 for a great number of drugs, 218 00:13:17,760 --> 00:13:21,960 and that's what this table lists. 219 00:13:21,960 --> 00:13:26,960 So here we're calling abacavir, there's an HLAB biomarker 220 00:13:28,680 --> 00:13:30,510 because there's a boxed warning 221 00:13:30,510 --> 00:13:34,470 as Abacavir in certain HLAB types, 222 00:13:34,470 --> 00:13:38,523 can lead to life-threatening adverse reactions. 223 00:13:41,220 --> 00:13:43,740 We've talked about the antidepressants 224 00:13:43,740 --> 00:13:45,900 and they're saying precautions. 225 00:13:45,900 --> 00:13:48,900 So there may be some things you can learn from CYP2D6 226 00:13:48,900 --> 00:13:50,700 that you may wanna take precautions. 227 00:13:51,690 --> 00:13:54,540 And there are other kinds of things. 228 00:13:54,540 --> 00:13:56,460 Here's clinical pharmacology. 229 00:13:56,460 --> 00:14:00,540 Just, you need to know that UGT1A1 is involved 230 00:14:00,540 --> 00:14:05,540 in the elimination of arformoterol, for example. 231 00:14:05,730 --> 00:14:08,160 So there are different levels here, down here, 232 00:14:08,160 --> 00:14:09,780 warning and precautions. 233 00:14:09,780 --> 00:14:13,230 So there's different levels that you need to be aware of. 234 00:14:13,230 --> 00:14:16,230 You can link on this, on the individual drug name 235 00:14:16,230 --> 00:14:18,153 to get to the drug labels. 236 00:14:19,650 --> 00:14:21,450 You can also download the detailed version 237 00:14:21,450 --> 00:14:25,410 of this table, which has the labeling text in it. 238 00:14:25,410 --> 00:14:26,730 And I won't do that at this point, 239 00:14:26,730 --> 00:14:29,460 but you can download that. 240 00:14:29,460 --> 00:14:34,460 This table is updated every time a drug gets updated 241 00:14:34,530 --> 00:14:38,610 in its biomarker information 242 00:14:38,610 --> 00:14:41,880 or the level of warning that the table gets updated 243 00:14:41,880 --> 00:14:43,350 whenever a new drug is approved 244 00:14:43,350 --> 00:14:45,603 with a biomarker attached to the approval. 245 00:14:46,440 --> 00:14:48,657 So this is a really good place to look 246 00:14:48,657 --> 00:14:51,060 and it's basically one long webpage, 247 00:14:51,060 --> 00:14:53,850 so you can do a control F on the webpage 248 00:14:53,850 --> 00:14:56,010 to find the medication that you're interested in 249 00:14:56,010 --> 00:14:57,990 or the genes that you're interested in. 250 00:14:57,990 --> 00:15:00,900 That's the way to search this page, okay? 251 00:15:00,900 --> 00:15:03,393 So down to the bottom, warfarin, et cetera. 252 00:15:05,040 --> 00:15:06,900 So I'm gonna stop there. 253 00:15:06,900 --> 00:15:07,920 Those are two websites 254 00:15:07,920 --> 00:15:10,830 which are really extraordinarily helpful 255 00:15:10,830 --> 00:15:13,980 in looking up authoritative information on what 256 00:15:13,980 --> 00:15:18,980 to do with pharmacogenomic information. 257 00:15:19,410 --> 00:15:21,813 Thank you and thank you for learning.