1 00:00:08,942 --> 00:00:10,710 Welcome to tonight's course. 2 00:00:10,710 --> 00:00:14,748 My name is Liz Ness and I'm an educator 3 00:00:14,748 --> 00:00:18,785 in clinical research with the NCI's intramural research program. 4 00:00:18,785 --> 00:00:22,789 I do bring over 20 years of research experience, 5 00:00:22,789 --> 00:00:26,393 so hopefully there's a little bit of credibility 6 00:00:26,393 --> 00:00:31,765 to what I'm going to be speaking with you about this evening. 7 00:00:31,765 --> 00:00:36,236 I functioned in a role as a research nurse coordinator, 8 00:00:36,236 --> 00:00:42,042 as well as some sponsor-related roles, and now, the role of an educator. 9 00:00:42,042 --> 00:00:45,178 So, I'll be talking with you tonight 10 00:00:45,178 --> 00:00:48,314 about quality management in clinical research. 11 00:00:48,314 --> 00:00:51,451 And so, when I think of 12 00:00:51,451 --> 00:00:55,055 quality management, it's really the soup to nuts. 13 00:00:55,055 --> 00:00:59,526 It's looking at establishing and ensuring that we have processes 14 00:00:59,526 --> 00:01:02,662 through all of the aspects of clinical 15 00:01:02,662 --> 00:01:05,799 research: protocol development, documentation, data, data analysis. 16 00:01:05,799 --> 00:01:08,501 And it is a multidisciplinary activity. 17 00:01:08,501 --> 00:01:13,440 It's done by the entire research team, as well as others. 18 00:01:13,440 --> 00:01:17,911 And it is not something that occurs just at one moment in time. 19 00:01:17,911 --> 00:01:22,382 And there is a trend now that a lot of the quality management 20 00:01:22,382 --> 00:01:25,485 programs are looking at being risk-based management: so, looking 21 00:01:25,485 --> 00:01:28,588 at the overall risk level of a particular study 22 00:01:28,588 --> 00:01:32,358 and then developing a quality management plan that would be appropriate 23 00:01:32,358 --> 00:01:33,726 for that risk level. 24 00:01:33,726 --> 00:01:36,496 And we'll talk a little bit about that. 25 00:01:37,297 --> 00:01:42,035 So, when I think of the -- of quality management, 26 00:01:42,035 --> 00:01:45,805 you know, I think of providing quality data 27 00:01:45,805 --> 00:01:49,609 and ensuring the protection of our research participants. 28 00:01:49,609 --> 00:01:53,379 And that basically translates into good clinical practice. 29 00:01:53,379 --> 00:01:58,118 So, if we're following our standards for good clinical practice, 30 00:01:58,118 --> 00:02:02,355 then we really shouldn't have many issues in terms 31 00:02:02,355 --> 00:02:07,560 of the quality of the research that we are conducting. 32 00:02:07,560 --> 00:02:11,798 The International Conference on Harmonization, in their guidelines, 33 00:02:11,798 --> 00:02:15,602 they do address some quality issues in terms 34 00:02:15,602 --> 00:02:21,741 of that all the clinical trial information should be recorded, handled, and stored 35 00:02:21,741 --> 00:02:26,980 that is in a way that is accurate, that you can report it 36 00:02:26,980 --> 00:02:30,617 properly, you can interpret it, you can verify it. 37 00:02:30,617 --> 00:02:35,054 You need to have systems in place that assure the quality 38 00:02:35,054 --> 00:02:39,092 of every aspect of the trial, and that quality control 39 00:02:39,092 --> 00:02:44,330 is applied to all stage, in particular, of the data handling processes. 40 00:02:44,330 --> 00:02:46,766 In terms of the U.S. 41 00:02:46,766 --> 00:02:51,271 and the FDA regulations around quality, they don't really 42 00:02:51,271 --> 00:02:56,776 come out, per se, and address quality as ICH guidelines do. 43 00:02:56,776 --> 00:03:01,781 But the investigators' responsibilities, as it relates to investigational drugs 44 00:03:01,781 --> 00:03:06,786 and devices, certainly talks about adhering to our GCP standards 45 00:03:06,786 --> 00:03:12,292 in conducting a trial and, in terms of the sponsor's responsibility, 46 00:03:12,292 --> 00:03:15,795 does address selecting appropriate and training investigators, 47 00:03:15,795 --> 00:03:21,301 as well as monitors, and monitoring the progress of the study. 48 00:03:21,534 --> 00:03:25,171 So, there's no real regulations that are wrapped 49 00:03:25,171 --> 00:03:31,544 around the concept of quality management that jumps out at you in the regulations, 50 00:03:31,544 --> 00:03:34,247 but they're implied in many aspects 51 00:03:34,247 --> 00:03:38,351 of the regulations and the FDA's guidance documents. 52 00:03:38,351 --> 00:03:44,724 So, there's just three sort of quality terms that I want to address. 53 00:03:44,724 --> 00:03:48,795 And sometimes we use these two somewhat interchangeably: quality 54 00:03:48,795 --> 00:03:50,630 control and quality assurance. 55 00:03:50,630 --> 00:03:54,934 And so, you can see here the definition of quality assurance. 56 00:03:54,934 --> 00:03:58,037 It's sort of a planned, systematic, independent evaluation 57 00:03:58,037 --> 00:04:01,941 of trial-related activities and it documents that the data is 58 00:04:01,941 --> 00:04:05,078 verifiable, that it's been collected, handled, and analyzed 59 00:04:05,078 --> 00:04:09,349 according to the regulations, the protocol, as well as SOPs. 60 00:04:09,349 --> 00:04:14,821 So, some of the things here that you need to think about is 61 00:04:14,821 --> 00:04:20,293 do you have SOPs in terms of how you manage the quality and handle 62 00:04:20,293 --> 00:04:24,964 all the various aspects of the development of a clinical research study, 63 00:04:26,432 --> 00:04:28,668 are you developing training logs 64 00:04:28,668 --> 00:04:32,672 and reviewing to ensure that there is appropriate training? 65 00:04:32,672 --> 00:04:37,577 In terms of quality control, I think of this as something 66 00:04:37,577 --> 00:04:42,482 that we should be doing 100 percent of the time, so 67 00:04:42,482 --> 00:04:46,953 that we're constantly looking at the data that's being generated; 68 00:04:46,953 --> 00:04:51,391 we're constantly revising our SOPs; we may be developing checklists; 69 00:04:51,391 --> 00:04:55,862 we may be developing, you know, temperature logs for freezers 70 00:04:55,862 --> 00:05:01,834 so that we have alarm and log processes, as it relates to biospecimen repositories. 71 00:05:01,834 --> 00:05:07,440 So, these are sort of things I think of in terms of quality control 72 00:05:07,440 --> 00:05:13,079 as what we're always doing so that we all have some aspect of that. 73 00:05:13,079 --> 00:05:18,284 If I'm a provider, I want to make sure that I have quality 74 00:05:18,284 --> 00:05:21,921 progress notes on a research participant, there's quality documentation 75 00:05:21,921 --> 00:05:25,124 to start quality data management types of activities. 76 00:05:25,758 --> 00:05:28,795 And the result of both quality assurance and quality 77 00:05:28,795 --> 00:05:31,164 control is really this concept of quality improvement. 78 00:05:31,831 --> 00:05:35,201 So, you're trying to identify those trends and areas for improvement. 79 00:05:35,201 --> 00:05:38,237 You may have had some type of sentinel event 80 00:05:38,237 --> 00:05:41,274 that required you to do a root cause analysis 81 00:05:41,274 --> 00:05:44,310 and to develop a corrective and preventative action plan. 82 00:05:44,310 --> 00:05:47,013 And you want to identify, then, solutions. 83 00:05:47,013 --> 00:05:50,383 And usually education and training is always one thing 84 00:05:50,383 --> 00:05:54,420 that you can be guaranteed of should be part of your plan. 85 00:05:54,420 --> 00:05:57,457 Because most people don't do things because they know 86 00:05:57,457 --> 00:06:02,195 they should be doing it one way and they choose to do it another way. 87 00:06:02,528 --> 00:06:05,231 Most of the time, it's just that 88 00:06:05,231 --> 00:06:08,334 lack of knowledge or that lack of education. 89 00:06:08,334 --> 00:06:11,437 And it may be specific to a protocol. 90 00:06:11,437 --> 00:06:14,540 It may be specific to a particular timepoint 91 00:06:14,540 --> 00:06:17,844 in the lifecycle of a clinical research study. 92 00:06:17,844 --> 00:06:22,682 So, every protocol needs to have a data and safety monitoring plan. 93 00:06:22,682 --> 00:06:28,488 Okay, we need to figure out a way that we can ensure good clinical practice. 94 00:06:28,755 --> 00:06:33,192 It does need to be tailored to the type of study 95 00:06:33,192 --> 00:06:37,263 or the risk of the study, the size, the complexity. 96 00:06:37,263 --> 00:06:40,900 And it needs to be described in the protocol 97 00:06:40,900 --> 00:06:44,137 or in the protocol application to the IRB. 98 00:06:44,137 --> 00:06:50,410 So, the IRB needs to approve what the data and safety monitoring plan actually is. 99 00:06:50,410 --> 00:06:53,846 So, some of the elements of a DSMP 100 00:06:53,846 --> 00:06:57,083 is that you need to identify the roles 101 00:06:57,083 --> 00:07:00,720 and responsibilities for gathering, evaluating, and monitoring the data. 102 00:07:00,720 --> 00:07:05,191 What type of monitoring mechanism are you going to be using? 103 00:07:05,191 --> 00:07:08,194 Do you need an individual medical monitor? 104 00:07:08,194 --> 00:07:13,299 Do you need a data monitoring committee, a data safety monitoring board, 105 00:07:13,299 --> 00:07:17,570 which I know has already been discussed in the series? 106 00:07:17,570 --> 00:07:21,808 What's the frequency of that safety monitoring going to be? 107 00:07:21,808 --> 00:07:24,377 What are you going to monitor? 108 00:07:24,377 --> 00:07:27,780 What are you going to be looking at? 109 00:07:27,780 --> 00:07:32,485 And how frequently and when should this monitoring process start? 110 00:07:32,485 --> 00:07:38,024 The plan also needs to identify what are the roles and responsibilities 111 00:07:38,024 --> 00:07:39,725 of the research staff, 112 00:07:39,725 --> 00:07:43,563 the investigator, the sponsor, maybe the entity who's monitoring. 113 00:07:43,563 --> 00:07:48,234 Maybe it's a sponsor who is using a contract research organization 114 00:07:48,234 --> 00:07:52,071 as their element of a data safety monitoring plan. 115 00:07:52,371 --> 00:07:57,777 And are -- do there need to be plans for any type of interim analysis? 116 00:07:57,777 --> 00:08:01,013 You know, maybe there is an early stopping rule 117 00:08:01,013 --> 00:08:04,617 in the protocol or some other type of change rules. 118 00:08:04,617 --> 00:08:10,723 So, that all needs to be sort of built-in to a data and safety monitoring plan. 119 00:08:10,723 --> 00:08:15,061 So, the way that we get at sort of quality management 120 00:08:15,061 --> 00:08:19,732 and what type of data and safety monitoring plans we're going to be 121 00:08:19,732 --> 00:08:23,336 using is looking at the concepts of auditing and monitoring. 122 00:08:23,603 --> 00:08:27,773 And these terms, also, are very often used interchangeably. 123 00:08:27,773 --> 00:08:31,477 And the way that I think of it 124 00:08:31,477 --> 00:08:34,747 is auditing is looking at the forest, 125 00:08:34,747 --> 00:08:39,852 whereas monitoring is looking at a tree, all of its branches, 126 00:08:39,852 --> 00:08:44,957 all of this leaves, you know, so we're looking more granular. 127 00:08:44,957 --> 00:08:49,128 So, monitoring might be looking at 100 percent source 128 00:08:49,128 --> 00:08:54,233 document verification of the data that's being provided to a sponsor 129 00:08:54,233 --> 00:08:59,805 compared to what is in the medical record and the research record 130 00:08:59,805 --> 00:09:05,244 for a research participant, whereas auditing may be looking at certain 131 00:09:05,244 --> 00:09:10,082 elements, such as the informed consent process, eligibility, adverse events; so, 132 00:09:10,082 --> 00:09:13,152 they're not going to look at 100 133 00:09:13,152 --> 00:09:16,689 percent of the source documents and verify those. 134 00:09:16,689 --> 00:09:19,759 So, one's a little bit broader picture; 135 00:09:19,759 --> 00:09:22,828 the other is a very focused picture. 136 00:09:22,828 --> 00:09:26,799 And, together, you end up with a solid quality 137 00:09:26,799 --> 00:09:30,770 assurance or quality management plan for a clinical trial. 138 00:09:31,604 --> 00:09:34,974 So, there's going to be different 139 00:09:34,974 --> 00:09:38,344 types of these plans, monitoring plans. 140 00:09:38,344 --> 00:09:42,815 There's PI and the research team have responsibilities. 141 00:09:42,815 --> 00:09:46,719 The organization, the institution needs to have 142 00:09:46,719 --> 00:09:51,757 some type of quality assurance plan or monitoring strategies. 143 00:09:51,757 --> 00:09:56,796 The sponsor, whoever holds the investigational new drug IDE 144 00:09:56,796 --> 00:10:01,867 or IND application, they need to have a plan. 145 00:10:01,867 --> 00:10:06,906 Also, there may be a need for independent monitoring, 146 00:10:06,906 --> 00:10:11,377 and our regulatory organizations also have this concept 147 00:10:11,377 --> 00:10:14,747 of some type of a quality 148 00:10:14,747 --> 00:10:17,550 monitoring or quality management plan. 149 00:10:17,850 --> 00:10:24,090 And I'll give some examples of each of these and then talk about sort 150 00:10:24,090 --> 00:10:28,527 of how we prepare for any one of these individuals 151 00:10:28,527 --> 00:10:31,664 to come and do an onsite visit 152 00:10:31,664 --> 00:10:35,901 and look at the quality of our clinical research. 153 00:10:35,901 --> 00:10:40,573 So, the PI is personally responsible for conducting and supervising 154 00:10:40,573 --> 00:10:45,044 a clinical research study, and they are able to delegate 155 00:10:45,044 --> 00:10:49,081 certain responsibilities, and those do need to be identified. 156 00:10:49,081 --> 00:10:53,986 The team should meet on a regular basis and make decisions 157 00:10:53,986 --> 00:10:57,556 about enrollment, review adverse events, review response data. 158 00:10:57,556 --> 00:11:02,461 All of the data should be collected in a timely manner 159 00:11:02,461 --> 00:11:06,032 and the PI should be reviewing that data. 160 00:11:06,599 --> 00:11:12,271 There's going to be some, you know, need to address adverse advent 161 00:11:12,271 --> 00:11:14,173 reporting, noncompliance reporting, protocol 162 00:11:14,173 --> 00:11:17,977 deviation reporting, and also doing a statistical review. 163 00:11:17,977 --> 00:11:22,248 So, those are all components that the research needs 164 00:11:22,248 --> 00:11:26,752 to have in place and needs to be outlined. 165 00:11:26,752 --> 00:11:30,790 The organization itself, such as an individual institute 166 00:11:30,790 --> 00:11:36,962 or center here within the NIH community or a larger academic medical center, 167 00:11:36,962 --> 00:11:42,201 they're going to have some type of an organizational QA plan 168 00:11:42,201 --> 00:11:45,071 to really begin to look at quality. 169 00:11:45,971 --> 00:11:49,475 Most often, these are going to be risk-based. 170 00:11:49,475 --> 00:11:54,714 So, a higher risk will have a different, maybe, frequency of monitoring, 171 00:11:54,714 --> 00:11:57,750 as well as the degree of what 172 00:11:57,750 --> 00:12:01,687 gets looked at or what gets audited or inspected. 173 00:12:01,687 --> 00:12:04,290 There's a lot of interchanging of 174 00:12:04,290 --> 00:12:08,461 terminology we often use when we talk about quality. 175 00:12:08,461 --> 00:12:13,032 So, they're going to -- an organization's going to identify 176 00:12:13,032 --> 00:12:17,837 some aspect of GCP that needs to have a quality review. 177 00:12:17,837 --> 00:12:23,375 They may do this based on prior deficiencies that have been noted. 178 00:12:23,375 --> 00:12:27,546 They may be implementing a new standard operating procedure, 179 00:12:27,546 --> 00:12:31,684 and so they want to do a preassessment implement 180 00:12:31,684 --> 00:12:35,855 with training and education, and then do a post-assessment. 181 00:12:35,855 --> 00:12:39,992 Maybe they never had a delegation SOP before in 182 00:12:39,992 --> 00:12:44,630 what the PI is allowed to delegate and to whom. 183 00:12:44,630 --> 00:12:48,768 So, maybe they want to assess delegation beforehand, implement 184 00:12:48,768 --> 00:12:54,774 a SOP, a policy, and then, you know, audit that and see how 185 00:12:54,774 --> 00:12:58,944 well the SOP and compliance with that is working. 186 00:12:59,512 --> 00:13:04,650 So, they do need to think about developing some type of a matrix 187 00:13:04,650 --> 00:13:09,421 and using that data for quality improvement across the organization level. 188 00:13:09,421 --> 00:13:14,160 Often in many of the academic medical centers and certainly here 189 00:13:14,160 --> 00:13:18,931 within the intramural community, we do a lot of clinical research studies 190 00:13:18,931 --> 00:13:23,669 that do not fall under the category of being a clinical trial. 191 00:13:23,669 --> 00:13:28,440 And, often, those are not, you know, those are using investigational drugs 192 00:13:28,440 --> 00:13:33,579 or devices where there'd be a sponsor that would be responsible for monitoring. 193 00:13:33,979 --> 00:13:40,553 So, maybe the organization wants to look at those clinical research studies 194 00:13:40,553 --> 00:13:46,025 that are not clinical trials and ensure that informed consent 195 00:13:46,025 --> 00:13:51,764 was appropriately obtained and documented and that the individual's eligible for 196 00:13:52,331 --> 00:13:58,070 the clinical research study, some example -- an example of what 197 00:13:58,070 --> 00:14:01,373 the organization may want to consider 198 00:14:01,373 --> 00:14:06,011 as one type of a matrix to evaluate. 199 00:14:06,011 --> 00:14:10,950 Sponsored clinical trials, those that hold an IND or an IDE, 200 00:14:10,950 --> 00:14:15,821 there are regulations around the fact that the sponsor does need to monitor. 201 00:14:15,821 --> 00:14:19,558 But, again, the FDA is not prescriptive about the frequency 202 00:14:19,558 --> 00:14:23,329 of that monitoring or, you know, what is really appropriate. 203 00:14:23,329 --> 00:14:26,332 They do leave that up to the sponsor. 204 00:14:26,332 --> 00:14:29,702 And, here, the sponsor can be an individual investigator. 205 00:14:29,702 --> 00:14:33,806 And if that investigator is a sponsor, then not only does 206 00:14:33,806 --> 00:14:38,310 he have his own research team and PI plan that they need 207 00:14:38,310 --> 00:14:42,448 -- he needs to develop, he or she needs to develop, 208 00:14:42,448 --> 00:14:45,818 but it's also going to have the sponsor plan: 209 00:14:46,218 --> 00:14:50,422 what's that going to be, who's going to be an independent body 210 00:14:50,422 --> 00:14:55,327 that's going to come in and take a look at the data, in particular? 211 00:14:55,327 --> 00:14:59,164 Or, it can be your other traditional government agency, pharmaceutical company. 212 00:14:59,164 --> 00:15:03,002 And most of the time, certainly within the clinical trial world, 213 00:15:03,002 --> 00:15:06,338 a lot of it is with the biopharmaceutical industry. 214 00:15:06,338 --> 00:15:10,376 But there are various types of site visits that most sponsors 215 00:15:10,376 --> 00:15:11,410 will traditionally make. 216 00:15:11,410 --> 00:15:16,916 And so, I just wanted to review some of those because they do 217 00:15:16,916 --> 00:15:20,719 -- are impacted with the sponsor's quality management plan. 218 00:15:20,719 --> 00:15:25,791 So, a sponsor will often do what's referred to as a pre-study 219 00:15:25,791 --> 00:15:30,429 qualification visit, where they're actually coming in, looking at the site, 220 00:15:30,429 --> 00:15:34,667 meeting with the research team, seeing where the investigational product 221 00:15:34,667 --> 00:15:38,470 will be stored, seeing where the infusion will occur. 222 00:15:39,271 --> 00:15:42,474 So, they're really assessing the site to make sure 223 00:15:42,474 --> 00:15:46,345 that the site is qualified, and that the investigator is qualified. 224 00:15:46,345 --> 00:15:51,650 And they may even be looking to see if that investigator has a study coordinator. 225 00:15:52,351 --> 00:15:54,820 This usually is a few hour visit, 226 00:15:54,820 --> 00:15:59,058 and they also usually like to have a tour of the facility. 227 00:15:59,058 --> 00:16:01,894 They may even, if biospecimens are being collected, 228 00:16:01,894 --> 00:16:05,764 they may even want to see where those are being stored. 229 00:16:06,298 --> 00:16:10,736 They may want to see the freezer, you know, alarm policy. 230 00:16:10,736 --> 00:16:16,008 So, they have a right to do that because they need to ensure 231 00:16:16,008 --> 00:16:20,245 that the study is being placed at an appropriate site. 232 00:16:20,245 --> 00:16:23,682 And then, once that site has been selected, 233 00:16:23,682 --> 00:16:27,319 the protocol has gone through the IRB approval process, 234 00:16:27,319 --> 00:16:31,790 then there'll be what's referred to as a site initiation visit. 235 00:16:31,790 --> 00:16:33,392 And that's usually performed 236 00:16:33,392 --> 00:16:37,529 by a clinical research association, also known as a monitor. 237 00:16:37,529 --> 00:16:43,469 And it doesn't include the PI, as well as members of the research team. 238 00:16:43,469 --> 00:16:48,574 And this is really to review the protocol, to review required procedures 239 00:16:48,574 --> 00:16:52,811 within the protocol, to review adverse advent reporting, to review 240 00:16:52,811 --> 00:16:58,350 just to make sure that everybody understands what is supposed to be done, 241 00:16:58,350 --> 00:17:03,022 the specific timeframes, as well as how data will be collected. 242 00:17:03,389 --> 00:17:09,061 It may include training on remote data capture systems for a research database. 243 00:17:09,061 --> 00:17:16,001 And so, this will vary, but a lot of times this will take a full day. 244 00:17:16,001 --> 00:17:20,472 So, members of the research team, such as a study coordinator, 245 00:17:20,472 --> 00:17:24,943 or if you're fortunate enough to have a clinical data manager, 246 00:17:24,943 --> 00:17:29,415 they would need to plan to be there the whole time. 247 00:17:29,982 --> 00:17:33,252 Pharmacists would need to be there when discussing 248 00:17:33,252 --> 00:17:38,157 the drug product itself if this is, you know, an IND study. 249 00:17:38,157 --> 00:17:43,462 So, it's another type of visit that, you know, really serves to prevent 250 00:17:43,462 --> 00:17:47,533 possible errors from occurring because they're sort of planning ahead 251 00:17:47,533 --> 00:17:51,203 and trying to iron out all of the questions 252 00:17:51,203 --> 00:17:56,942 that the site might have or that the sponsor may have about the site 253 00:17:56,942 --> 00:18:00,212 that didn't come up in the pre-initiation visit. 254 00:18:01,013 --> 00:18:04,883 And then, periodically, the monitor or the CRA 255 00:18:04,883 --> 00:18:09,254 is going to come and do onsite monitoring visits. 256 00:18:09,254 --> 00:18:13,125 And these, again, will be based on the 257 00:18:13,125 --> 00:18:17,463 risk of the study, the complexity of the study. 258 00:18:17,463 --> 00:18:22,801 The sponsor will have developed their own SOPs related to this. 259 00:18:22,801 --> 00:18:26,205 Early phase studies are often have onsite 260 00:18:26,205 --> 00:18:30,075 monitoring visits more frequently than phase three studies. 261 00:18:30,843 --> 00:18:36,014 They also may have not only an onsite audit program or monitoring program, 262 00:18:36,014 --> 00:18:40,752 but they may also, through remote data captures, you know, clinical data 263 00:18:40,752 --> 00:18:44,723 management systems, be doing continual monitoring of the data coming 264 00:18:44,723 --> 00:18:49,061 in, looking for those logical things, things that don't make sense. 265 00:18:49,061 --> 00:18:53,832 They said they had a fever as an adverse event, but, yet, 266 00:18:53,832 --> 00:18:57,002 the temperature was normal, those kinds of things. 267 00:18:57,336 --> 00:19:02,107 So, they're going to have a set SOP and they're going to -- 268 00:19:02,107 --> 00:19:06,145 the FDA will hold them accountable for what that SOP is. 269 00:19:06,145 --> 00:19:07,246 And so, typically, 270 00:19:07,246 --> 00:19:12,017 these visits do this 100 percent source document verification plan, if you will. 271 00:19:12,017 --> 00:19:15,721 And then, at the end of each of these visits, 272 00:19:15,721 --> 00:19:21,226 there's usually some type of a summary by the CRA to explain, you know, how 273 00:19:21,226 --> 00:19:25,998 well the site is doing or identifying areas for them to improve on. 274 00:19:25,998 --> 00:19:28,934 So, again, it's all about quality. 275 00:19:28,934 --> 00:19:35,474 And then, the last visit that a sponsor will do is a closeout visit. 276 00:19:35,474 --> 00:19:41,346 And this is when the study has been completely closed with the IRB; 277 00:19:41,346 --> 00:19:47,219 there's no patients left on the study; all the data has been analyzed; 278 00:19:47,219 --> 00:19:53,091 and all of the sponsor's supplies, whether they be drug, device, lab specimen 279 00:19:53,091 --> 00:19:57,596 kits, whatever they've given has either been returned or destroyed 280 00:19:57,596 --> 00:20:01,667 according to what the sponsor's standard operation procedures are. 281 00:20:01,667 --> 00:20:04,636 And they'll do review of regulatory documents. 282 00:20:04,636 --> 00:20:07,573 And then, they typically remind the investigator 283 00:20:07,573 --> 00:20:10,542 about the FDA's record retention requirements. 284 00:20:10,542 --> 00:20:15,180 A sponsor also may come in and conduct an audit. 285 00:20:15,180 --> 00:20:18,550 So, they've already been in doing monitoring visits. 286 00:20:18,550 --> 00:20:21,920 What possibly more could they want to do? 287 00:20:21,920 --> 00:20:26,158 Well, they may come in to do a monitoring visit 288 00:20:26,158 --> 00:20:30,362 because their product is now in the marketing application process. 289 00:20:30,662 --> 00:20:36,468 And so, they want to come to a site that maybe had some high accruers. 290 00:20:36,468 --> 00:20:40,339 They want to make sure that everything is in order 291 00:20:40,339 --> 00:20:44,977 for when the FDA may choose to come and inspect the site. 292 00:20:45,777 --> 00:20:51,183 So, the FDA will come and inspect sites before they actually will grant approval 293 00:20:51,183 --> 00:20:55,053 of a product as part of their quality management program. 294 00:20:55,387 --> 00:20:58,557 They also, as part of their QA 295 00:20:58,557 --> 00:21:01,727 program, will come in sometimes to audit 296 00:21:01,727 --> 00:21:07,132 the monitor to ensure that the monitor is, in fact, doing what 297 00:21:07,132 --> 00:21:11,670 they're supposed to be doing according to that sponsor's SOPs. 298 00:21:11,670 --> 00:21:15,741 So, again, it's all about -- it's not meant 299 00:21:15,741 --> 00:21:18,877 punitively, it's all about ensuring quality. 300 00:21:18,877 --> 00:21:22,047 So, we've talked a little bit 301 00:21:22,047 --> 00:21:28,387 about what the PI's plan is, the research team plan, what an individual institution 302 00:21:28,387 --> 00:21:32,891 or organization's QA plan needs to be for clinical research. 303 00:21:33,292 --> 00:21:36,862 Talked about sort of the sponsor's plan, in terms 304 00:21:36,862 --> 00:21:41,633 of the types of visits, as well as the auditing that's done. 305 00:21:41,633 --> 00:21:46,805 And so, we have left sort of this independent monitoring or data safety 306 00:21:46,805 --> 00:21:51,176 monitoring board, which is somewhat tied- in to the sponsor's plan 307 00:21:51,176 --> 00:21:53,178 sometimes or even the organization's 308 00:21:53,178 --> 00:21:57,149 plan, depending upon funding, and then, our regulatory groups. 309 00:21:57,149 --> 00:22:02,321 So, a sponsor or an organization may choose, or a PI, 310 00:22:02,721 --> 00:22:06,692 may choose to have an independent monitor for a study 311 00:22:06,692 --> 00:22:11,063 that might be more than minimal risk; or for a study 312 00:22:11,063 --> 00:22:15,834 that uses more than one site; or if the investigator could have 313 00:22:15,834 --> 00:22:20,505 a potential conflict of interest, though nowadays our conflict of interest 314 00:22:20,505 --> 00:22:24,509 policies are pretty strict and they most likely wouldn't 315 00:22:24,509 --> 00:22:29,414 be allowed to be a PI; and with some FDA-regulated research. 316 00:22:29,414 --> 00:22:33,885 Sometimes an independent monitor could be selected to help guide 317 00:22:33,885 --> 00:22:38,323 phase one dose escalation, looking at safety as an example. 318 00:22:38,323 --> 00:22:43,662 I know that the data safety monitoring board lecture has already occurred, 319 00:22:43,662 --> 00:22:48,133 so I'm not going to go into detail about that. 320 00:22:48,133 --> 00:22:53,038 But that's also another option that, depending upon your funding source 321 00:22:53,038 --> 00:22:57,476 and who the sponsor is, that may be a requirement, 322 00:22:57,476 --> 00:23:02,381 or it may be something that a sponsor chooses to do. 323 00:23:02,614 --> 00:23:08,387 So, we -- I've given a couple of acronyms: a DSMP and a DSMB. 324 00:23:08,387 --> 00:23:12,090 And it all becomes alphabet soup after a while. 325 00:23:12,090 --> 00:23:17,829 But I just wanted to show you that the data safety monitoring plan includes 326 00:23:17,829 --> 00:23:23,602 members of the research team, whereas a DSMB is separate from the research team, 327 00:23:23,602 --> 00:23:28,106 and that the data and safety monitoring plan needs to describe 328 00:23:28,106 --> 00:23:33,645 what's going to be reviewed, when, what the roles and responsibilities are. 329 00:23:33,645 --> 00:23:36,314 And a data safety monitoring board 330 00:23:36,314 --> 00:23:40,852 is going to do something similar, but it may be required. 331 00:23:40,852 --> 00:23:44,356 Remember, it's independent and it may be required 332 00:23:44,356 --> 00:23:47,426 based on your sponsor or your funding. 333 00:23:47,426 --> 00:23:52,664 And there are more phase three pivotal trials that industry is doing 334 00:23:52,664 --> 00:23:57,502 that is using a data safety monitoring board or the FDA 335 00:23:57,502 --> 00:24:02,507 guidance refers to them as actually data monitoring committees, or DMCs. 336 00:24:02,507 --> 00:24:06,244 So, if we look at our regulatory groups, 337 00:24:06,244 --> 00:24:09,314 they also have sort of monitoring programs 338 00:24:09,314 --> 00:24:12,384 looking at quality management and clinical research. 339 00:24:12,684 --> 00:24:15,887 And the FDA does what is called inspections 340 00:24:15,887 --> 00:24:19,491 -- you could think of it as an audit 341 00:24:19,491 --> 00:24:23,495 -- through their BIMO program, or their bioresearch monitoring program. 342 00:24:23,495 --> 00:24:28,733 And, again, if you look at what the goals are, all the goals 343 00:24:28,733 --> 00:24:33,138 point at good clinical practice or good clinical research practice. 344 00:24:33,138 --> 00:24:36,341 And the FDA has a nice information 345 00:24:36,341 --> 00:24:39,544 sheet that outlines what their monitoring program is. 346 00:24:39,544 --> 00:24:44,349 But they can do -- they will audit or inspect IRBs, investigators. 347 00:24:44,349 --> 00:24:47,552 They'll inspect for good not only clinical practice, 348 00:24:47,552 --> 00:24:51,957 but for good laboratory practice, as well as good manufacturing practices; 349 00:24:51,957 --> 00:24:57,128 so, all of the standards that they use in order to approve products. 350 00:24:57,929 --> 00:25:02,334 They may do these inspections as part of just something routine, 351 00:25:02,334 --> 00:25:08,306 or as part of a marketing application, or they may do them for a cause. 352 00:25:08,306 --> 00:25:10,709 So, there may be a reason. 353 00:25:10,709 --> 00:25:15,113 Someone may -- a sponsor may have concerns about an investigator, 354 00:25:15,113 --> 00:25:19,918 and they have not been able to secure compliance by that investigator. 355 00:25:19,918 --> 00:25:24,222 So, they might inform the FDA and the FDA 356 00:25:24,222 --> 00:25:28,994 may come in and do a for -- what's referred 357 00:25:28,994 --> 00:25:34,232 to as a "for cause" inspection, again, looking at quality, ensuring 358 00:25:34,232 --> 00:25:39,504 we have quality data, and we protect our human subjects. 359 00:25:39,504 --> 00:25:43,341 OHRP, or the Office for Human Research 360 00:25:43,341 --> 00:25:46,678 Protections, also has a compliance oversight program. 361 00:25:46,678 --> 00:25:50,982 And they will -- they're looking at obviously protecting 362 00:25:50,982 --> 00:25:55,287 and ensuring that the regulations that they are responsible 363 00:25:55,287 --> 00:25:56,221 for, oversights, 364 00:25:56,221 --> 00:26:00,759 overlooking at the human subjects protection regulations for the Department 365 00:26:00,759 --> 00:26:06,598 of Health and Human Services, fondly referred to as Title 45, Part 46. 366 00:26:06,598 --> 00:26:11,570 And they will also do routine or for cause inspections onsite, 367 00:26:11,570 --> 00:26:16,975 or they may actually follow-up via email or a phone call. 368 00:26:16,975 --> 00:26:21,479 Because anybody can, again, report some type of complaint. 369 00:26:21,479 --> 00:26:24,649 Maybe they didn't like a participant's 370 00:26:24,649 --> 00:26:28,486 family didn't like the outcome of their family member's participation 371 00:26:28,486 --> 00:26:32,724 on a clinical research study, or a clinical trial, in particular. 372 00:26:32,724 --> 00:26:36,928 Maybe it was a phase one study, they didn't really understand 373 00:26:36,928 --> 00:26:42,701 that the main goal was to assess the -- to determine the dose in humans. 374 00:26:42,701 --> 00:26:46,938 So, maybe they were upset, and they came off the study, 375 00:26:46,938 --> 00:26:50,775 and they didn't think that that was going to happen. 376 00:26:51,042 --> 00:26:54,179 They may send a complaint to OHRP. 377 00:26:54,179 --> 00:26:58,249 OHRP will follow-up on any of those complaints and, 378 00:26:58,249 --> 00:27:03,188 most of the time, sites are able to just explain things 379 00:27:03,188 --> 00:27:07,659 basically over the phone or via email to OHRP's satisfaction. 380 00:27:07,659 --> 00:27:13,965 If not, they'll they may come and choose to do an onsite inspection.