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<\/figure>\n\n\n\nDisclaimer: The examples noted in the\nfollowing are all firsthand accounts of the author, but for the purpose of this\narticle have been combined into a single site visit. The visit depicted below\nis an aggregate of many sites and studies and is not necessarily an exact\nrepresentation. The original version was written entirely on a smartphone while\nflying from Philadelphia to Puerto Rico.<\/em><\/p>\n\n\n\n\n\n\n\n As a\nclinical research monitor, a typical work week starts with me catching an Uber\nto the Philadelphia airport. I breeze through security with TSA pre-check and\nboard early with my frequent flyer status. While I am never in a rush to sit on\nan airplane any longer than necessary, boarding early to avoid fighting for\noverhead space for my suitcase is an easy tradeoff. It\u2019s a typical week for me,\nso I will only be in two cities this week: Miami then Charlotte. Both major\ncities with major airports so no connections to worry about and plenty to do if\nI happen to have some time to myself. <\/p>\n\n\n\n Spoiler\nalert, I won\u2019t. <\/p>\n\n\n\n If there are\nno flight delays, then I will get to my hotel at about 6 p.m. This will give me\nenough time to eat, hit the hotel gym to work off all the fast food I eat while\ntraveling, and prepare for my site visit the next day. I\u2019m preparing a bit more\nthan usual considering that I am covering tomorrow\u2019s visit for another CRA. The\nresearch site\u2019s original monitor recently quit – a common occurrence in a\nprofession with a 29% turnover rate!1<\/sup> I look over the report from\nthe previous visit, and everything at the site looks in order. The site had an\nissue in the beginning of the study with documenting the time of consent, but\ntheir monitor did some retraining and everything seems to be fine now. I have\nbeen on the study for several months, so I am confident that the visit will go\nsmoothly. I might even have enough time to eat lunch outside – wishful\nthinking.<\/p>\n\n\n\n I wake up at\n7:30 A.M. and arrive to the site at the appointment time, only to find the site\nisn\u2019t ready for me. Their previous monitor was usually an hour late, so they\nare surprised I arrived right at 9 A.M. \nAbout a half hour later, the site brings out the two six-inch thick\nbinders that make up their investigator site file and the one-inch binders that\nthey use for each of their twenty subjects.<\/p>\n\n\n\n It is time to do the real work of a CRA.<\/p>\n\n\n\n The previous\nmonitor finished the first six subjects and only checked the next three subjects\nfor enrollment eligibility, so I start with patient Number Ten. I will have to\ngo through the three subjects who were partially monitored, but I prefer to\nstart my day with a fresh subject to familiarize myself with how the site\ncaptures their data.<\/p>\n\n\n\n The CRO\n(Clinical Research Organization) I work for doesn\u2019t provide source\ndocumentation for the study, so every site does things a bit differently. This varied source creates inconsistencies\nin data capture<\/strong> and increases the\nmonitoring burden by forcing the CRA (me) to learn how each site operates<\/strong>.\nThis study is small for a phase III, with only about 50 research sites in the\nU.S. and Canada conducting visits and capturing data according to their own\ndifferent SOPs. Phase III studies are sophisticated operations and are\nincreasing in complexity,2<\/sup> so the chances that 50 different sites\nperfectly capture all the data that we need are close to zero. In addition to\ncomplexities of the study itself, these 50 sites were trained by 10 different\nCRAs on a protocol that has been amended twice before the study even started. We\nare now focused on capturing just minimum data we need to have the test product\napproved.<\/p>\n\n\n\n This is not\na criticism of my employer. I have worked for one small CRO and two of the\nlargest CROs, and they are all essentially the same. Not providing source\ndocumentation to sites for consistent data capture is industry standard\npractice.<\/p>\n\n\n\n This is a criticism of the industry.<\/strong> There are two reasons that I have\nidentified for why CROs don\u2019t provide source documentation to sites:<\/p>\n\n\n\n Personally,\nI believe that a CRO is hired for their expertise in clinical trials and should\nbe responsible for providing adequate source documentation to ensure that the\nstudy goes as smoothly as possible by promoting consistency in data capture. Adopting and providing standardized source documentation\nto sites reduces the workload not only on research sites, but also on the CRO\u2019s\nown staff of CRAs<\/strong>. <\/p>\n\n\n\n By having to familiarize myself with each site\u2019s method of source data capture, I not only eat into my limited time on site, but I am also less likely to recognize any trends across my sites, since they all capture the data differently. Noticing trends is a crucial part of clinical research monitoring, and it is vital to patient safety and good data quality. Because this is my first time at this site, it will be difficult to identify any trends while I acclimate myself to the site\u2019s patient visit binders. <\/p>\n\n\n\n I begin with\nsubject ten\u2019s consent form, which documents the procedures and study visits that\na patient will have to adhere to in the study. The consent form lists out the\npossible benefits, side effects, and alternative treatments. It also informs\nthe patient that he\/she can withdraw at any point, and it provides contact\ninformation for the patient in case they need more information.<\/p>\n\n\n\n The consent\nform is usually around twenty pages long but can vary depending on the\ncomplexity of the study. A patient must be consented prior to the initiation of\nany study procedures.3<\/sup> The consent process is a critical element of\nany legitimate research study, and ensuring proper consent is one of the main\nreasons why I have a job. Proper consent protects patients by keeping them\ninformed of risks and alternatives. When I monitor the consent process, I check\nthat each page of the most recently-approved consent form is present in the\npatient\u2019s chart and that the signature date matches the patient\u2019s first visit\ndate. Hopefully the site jots down a note with some details about the consent conversation\nwith the patient, or it at least uses a checklist that hits the bare minimum\npoints.<\/p>\n\n\n\n I can never truly know by simply\nchecking a signature and a note if the proper consent process happened; there\nis no way to know if the dates on the signature are accurate.<\/strong> Even if the date is accurate, I have\nno way of knowing if the consent process happened before any other study\nprocedures that day. As for the note about the consent conversation with the\npatient, it does not take a monitor long to notice that sites use standard\nlanguage. I suspect many sites have\nbecome much more proficient in documenting a proper consent process than\nactually performing proper consent. <\/strong><\/p>\n\n\n\n The previous\nmonitor already identified an issue with this site\u2019s consent process – the site\ndid not include a note detailing the consent discussion with the patient. The\nsite was retrained to include a note for each subject detailing this\nconversation. The patient\u2019s file that I am looking at has the following note:<\/p>\n\n\n\n \u201cPatient seen in office\ntoday for possible research study. Patient was given ample time to review the\nconsent form. Patient did not have any questions. Consent signed and copy\nprovided to patient. Consent performed\nprior to any study procedures.\u201d<\/em><\/p>\n\n\n\n Not perfect,\nbut better than a lot of notes that I have seen.<\/p>\n\n\n\n I take a\nquick peek back at patients one through nine to see if a note for each of their\nconsent discussions was added. No surprise, they each have the exact same note\nposted and dated to the day that the previous monitor was last on-site. While\nthese notes may be sufficient from a documentation standpoint, I find it hard\nto believe that the site was able to remember nine different conversations\nspanning over a month. It is even harder to believe that the ten patients\ndidn\u2019t have any questions about an investigational medicine for treatment of\ntheir HIV, especially since the treatment is for patients who were recently\ndiagnosed with HIV and likely to be na\u00efve regarding the disease.<\/p>\n\n\n\n I can ask the\nsite to clarify their consent process because I am having trouble believing the\naccuracy of the notes, but if the site says that none of the subjects had any\nquestions, I don\u2019t have any evidence to the contrary. I am forced to accept the industry standards for documenting consent.3<\/sup><\/strong><\/p>\n\n\n\n India\nrecently addressed the consent issue by requiring the consent process to be on\nvideo. Filming consent is much more effective at ensuring that the process was\nfollowed because a monitor can easily re-watch the entire process. However, the\nrevised video consent process had been met with resistance. Some doctors in\nIndian clinical trials argue that the requirement for being videotaped makes a\npatient less likely to enroll in a trial and hurts enrollment. <\/p>\n\n\n\n As an industry skeptic, I believe that\nthe push-back from doctors and the decrease in enrollment rates due to video\nconsent have a different source: fraud.<\/strong><\/p>\n\n\n\n It is much\nmore difficult to fabricate patient data and entire patients when video consent\nis required. The truth is likely\nsomewhere in between, but ample evidence exists across the globe proving that\nsome patients are fabricated.4, 5 <\/sup>As\na monitor, I have seen patient fabrication first hand and suspect that there\nhave been instances that I have missed. Industry leaders may argue that a video\nconsent process has potential to unblind patient data or increase the time of\nmonitoring. <\/p>\n\n\n\n To those experts I pose the following\nquestions: <\/strong><\/p>\n\n\n\n Currently there are no video consent requirements in the U.S. or for FDA submission, so I am forced to accept paper documentation at face value and move on to the patient\u2019s visit data. <\/p>\n\n\n\n The study for\nwhich I am on-site for today uses an eDiary that is provided to patients to\ncomplete some assessments, but it does not track dosing or side effects. Both\ndosing compliance and side effects are essential data, so not capturing them as\naccurately as possible in real time can be problematic.<\/p>\n\n\n\n As I read\nthrough patient Number Ten, I notice that at her last visit, she returned\nalmost all of her study medication unused. There are 30 days between each study\nvisit, and the patient returned 28 pills. \nProper dosing is once a day, so there is an obvious non-compliance in\ndosing but no way to determine exactly when the patient stopped properly\ndosing. The site reports that the subject stopped dosing 2 days after her\nprevious visit and that the site was not aware until the patient came in for\nher most recent visit 30 days later.<\/p>\n\n\n\n If the study recorded patient dosing\nelectronically, then the system could have been set up to automatically notify\nthe site of dosing noncompliance so that the site could have followed up with\nthe patient in real-time.<\/strong> Non-compliant dosing is particularly dangerous in studies such as HIV,\nas non-compliance in dosing can cause the patient to develop resistance to the\ntreatment and potentially to future treatments as well.8<\/sup><\/p>\n\n\n\n I read on to\ndetermine why the patient stopped taking her medicine. At her 30 day visit, the patient reported\nthat 28 days ago she felt that the medicine was making her nauseous. This side\neffect isn\u2019t uncommon in the study, but it can require some follow-up. In this\ninstance, it will require a lot of follow-up.<\/p>\n\n\n\n The site\nperforms a pregnancy test at each visit, and patient Number Ten\u2019s most recent\ntest is positive. Her nausea was not due\nto the medicine, but it was caused by her pregnancy.<\/strong> Now the site has a\npregnant woman at risk of developing resistance to HIV treatment for both\nherself and her unborn child. All of this could have been avoided if the eDiary\nreported dosing and side effects to the site in real-time. <\/p>\n\n\n\n The patient, site, and CRO would have\nbeen aware of the pregnancy in 3 days, and the patient would have had continued\ntreatment.<\/strong><\/p>\n\n\n\n At this\npoint, many sites and CROs are familiar with some kind of eCOA (electronic\nclinical outcomes and assessments) device, but current solutions present their\nown challenges. Supplying a large volume of sites with adequate diaries in a\nstudy with unpredictable enrollment can result in supply shortages. There is an\nadage in clinical trials that 80% of study enrollment will come from 20% of the\nsites on the study. With such a discrepancy in enrollment between sites, it can be difficult to forecast accurately\nto ensure adequate supply of product<\/strong>. Study supply shortages delay enrollment\nand greatly increase the costs of the study.6<\/sup> <\/p>\n\n\n\n BYOD (bring your own device)\nmitigates the problems associated with supplying sites with an eCOA device.<\/strong><\/p>\n\n\n\n Critics of\nBYOD will argue that many of the patients in Clinical Trials are economically\ndisadvantaged and are unlikely to have a smartphone necessary for BYOD.\nHowever, data in the\nfigure on the right7<\/sup> suggests that 50% of U.S. adults making\nless than $30,000 per year own a smartphone.<\/p>\n\n\n\n Critics of\neCOA argue that older patients have difficulties utilizing smart devices, but\nresearch shows that 73% of U.S. adults 50-64 own a smartphone.7<\/sup> <\/p>\n\n\n\n BYOD should\nfurther mitigate concerns with patients being unable to correctly capture eCOA\nby allowing them to use the devices with which they are already familiar. Not\nhaving to carry two smart devices also improves the chance of patients\nremembering to complete their assessments as required. BYOD is not without its own challenges. Any\nBYOD application needs to have a tested and proven UI (user interface) to ensure\nthat a diverse patient population will be able to complete all required\nassessments. While data suggests that most patients do have access to the\nrequired smartphones for BYOD, it is crucial to not exclude patients who do not\nown a personal smartphone. The best clinical trial management system should\nincorporate both BYOD and sponsor-supplied diaries to ensure that all potential\npatients can enroll.<\/p>\n\n\n\n While eCOA does not yet have the capability to send out real-time alerts, early adoption of this technology is a step in the right direction. A workaround to temporarily solve real-time alerts could be <\/strong>text-message reminders<\/strong> sent directly to your patients, alerting them to take the medication and fill out their diaries.<\/strong> Patients can respond to these text messages if they are experiencing any side effects, such as nausea, which will result in follow-up visits. <\/p>\n\n\n\n I will spend\nthe bulk of my day going through every data point the site has collected for\neach subject. I verify that the\ninformation is complete, accurate, makes logical sense, and was properly\nentered into the EDC system. When the EDC is properly set up prior to the study\nstart, this process can be as simple as just checking to ensure that the\nnumbers on the page match what\u2019s in the EDC system.<\/p>\n\n\n\n However, it is seldom this easy<\/strong>. In my experience, sites rarely have\na fully-functional EDC with good data validation and system queries in place\nprior to study start. Due to poor study foresight, tight timelines result in\nthe implementation of deficient study management systems. The CRA is\nresponsible to work with the site to mitigate the errors incurred as a result\nof any shortfalls. Errors are compounded by the fact that sites often enter\ndata into the EDC several days after patient visits occur. It is not uncommon\nfor a site to miss crucial study data points at the beginning of enrollment. <\/p>\n\n\n\n The need for\non-site monitoring of early study data is crucial to ensure that research sites\nare capturing all required data. Industry standards tend to require a visit\nwithin the first two weeks of enrollment. Unpredictable enrollment and a large\nsite load can make it difficult for a CRA to meet this crucial requirement.\nWith delayed EDC entry and required on-site monitoring, it can be anywhere from\nseveral days to months before a research site is even aware of a data\ndeficiency, which could potentially affect all of a site\u2019s patients up to that\npoint.<\/p>\n\n\n\n As I start\nto monitor patient Number Ten\u2019s study charts, I notice that the patient is\nmissing a date for his last HIV viral load. The site has recorded values based\non patient-reported data but does not have confirming lab reports with a viral\nload. While it is not uncommon to work from patient-reported medical history,\nthis study requires lab confirmation prior to enrollment. I take a quick peek\nback through subject Numbers One through Eight and see that this happened for five\npatients. The EDC system required a value, and the site did not notice the\nerror because they used the patient-reported value. The previous monitor missed\nit because the original protocol did not specify that sites needed to confirm\nviral load prior to enrollment. The update in protocol revision 1 clearly\nspecifies the change, but the site was activated on the original protocol and\nwas never retrained by their previous monitor.<\/p>\n\n\n\n Because this\nerror was not caught, I now need to tell the site that over half of their\npatients were enrolled in error and the site will not be paid for the work they\ndid with those patients.<\/p>\n\n\n\n The news gets worse.<\/strong><\/p>\n\n\n\n The site was\nalready paid for the patients, so the CRO will now be asking the site for over\nhalf of that money back. Protocol enrollment requirements are designed very specifically\nto protect patient safety \uff0d any patient enrolled in error can potentially\nendanger the patient and study integrity. The enrollment issue has now\nendangered five patients, provided unusable data, and cost the site and CRO a\nlot of time and money.<\/p>\n\n\n\n The worst part is that this problem\ncan be easily avoided.<\/strong><\/p>\n\n\n\n A relatively\nnew solution has arrived on the clinical trials scene: eSource<\/strong>. eSource comes in many forms, and there currently isn\u2019t a\none-size-fits-all solution. Each study in clinical trials presents unique\nproblems that require unique solutions.<\/p>\n\n\n\n Recently,\nmore complete eSource systems have emerged. New systems seek to eliminate all of the issues caused by the delay in\nCRA monitoring (and the costs that they incur to both sites and CROs).<\/strong> The\nsite where I am at today does not utilize eSource, so I will be paging through\nmultiple patient\u2019s visit binders all day. Each error that I find from simple\nmistakes, like using the wrong year in a date, to larger issues such as missing\ndata, needs to be addressed by the site staff while I am physically on-site.\nThe site staff have a regular workload while I am on-site, a workload that will\nbe continuously interrupted all day each time that I find a new issue that\nneeds to be addressed. This tension often leads to poor relations between a\nsite and their CRA, thus reducing the CRA\u2019s ability to serve effectively. <\/p>\n\n\n\n I notice\nthat the site has incorrectly completed all the dates on every visit for every\npatient using 2017. Recording the incorrect year is a common error with no real\nimpact on the data, but it still needs to be corrected. This error means that I\nwill be ruining the study coordinators\u2019 lunch time by having her correct the\ndate to 2018 on a couple of hundred pages. These corrections will be a\nfruitless task that would never occur if the site used a good eSource solution.\nA good eSource enters timestamps\nautomatically for each data point – the staff doesn\u2019t even have to enter a date,\nas the audit log captures all the required information.<\/strong><\/p>\n\n\n\n Timestamps\nthat include user signatures go a step further. With unique user accounts,\nevery data point is traceable back to its originator. Site staff do not have to\nwaste any time signing and dating, and instead, they can focus only on\nperforming the patient visit as quickly as possible. Expediting patient visits\nis critical as the industry moves towards more patient-centric trials. <\/p>\n\n\n\n Effective\neSource reduces the workload on sites by decreasing visit time and\ntranscription errors, thus freeing up site overhead to take on additional\nstudies.<\/p>\n\n\n\n As I sit at\nthe small desk in the makeshift office that I was given, pouring through pages\nof data to ensure that the site does not have any transcription errors, it\noccurs to me that eSource renders this entire process obsolete.<\/p>\n\n\n\n The greatest benefactor of eSource is\nthe CRO.<\/strong> Too often,\na monitor\u2019s time is spent fixing transcription errors that do not exist when\neSource is properly implemented. eSource enables the data to be pulled directly\ninto the EDC. This process dramatically reduces the workload on sites by\neliminating data entry and the need for QC\/QA for the data entry process.\nSource data validation can easily account for over 80% of a monitor\u2019s time.\nAfter eliminating the need for source data validation on-site by making the\nsource electronic, the monitor can focus on the larger issues of site\nenrollment, performance, and patient compliance, which can all be overlooked\nwith a high source validation workload.<\/p>\n\n\n\n Because the\nsite where I am did not utilize eSource, I will have to page through hundreds\nof papers to ensure that nothing is missing or incomplete. As I scramble to\nensure that I checked the bare minimum before I need to rush off to catch my\nflight, only to do it all again tomorrow in another city, I am struck with this\nthought: I love being a CRA, but the\nrole as it exists today is obsolete. <\/strong><\/p>\n\n\n\n By adopting\ncompletely electronic systems, 95% of the issues that I address won\u2019t exist.\nSay goodbye to transcription errors, and say goodbye to follow-up calls for\nmissing documentation. Most monitoring issues should be eliminated. The future\nof monitoring will be to focus on educating sites on the latest available\nsystems developed to reduce workload, improve patient safety, and increase\npatient engagement.<\/p>\n\n\n\n To the sites and CROs that haven\u2019t\nstarted to look at eSource, my advice is simple: start today.<\/strong><\/p>\n\n\n\n I believe that in ten years, clinical trials will be completely paperless. Complete eSystems will eliminate the existing inefficiencies. Average study length will decrease, and study workload for sites and CROs will drastically<\/em> decrease. Data safety and trends will be tracked in real-time using advanced analytics, making investigative trials as safe as possible for our patients. I believe that the latest technology will significantly reduce the cost of bringing new treatments to market, and it is my sincerest hope that the savings generated by more efficient clinical trials will be passed onto the people who truly matter in clinical trials: the patients<\/strong>.<\/p>\n\n\n\n 1) Brennan, Zachary. “Survey: CROs See\nRise in Employee Turnover Rate, Less Retention Bonuses.” Outsourcing-Pharma.com. William Reed\nBusiness Media SAS, 27 Mar. 2013. Web. 19 June 2017.<\/p>\n\n\n\n 2) Getz K. Rising clinical trial complexity\ncontinues to vex drug developers. (www.acrpnet.org). ACRP Wire. 13 May 2010.\nAccessed 20 June 2017.<\/p>\n\n\n\n 3) United States. FDA. 21 CFR Part 50 \u2013 Protection of Human\nSubjects. FDA, n.d. Web. 26 June 2017.<\/p>\n\n\n\n 4) Staff, RFA. “Chinese Clinical Trials\nData 80 Percent Fabricated: Government.” Radio Free Asia. Radio Free Asia, 27 Sept. 2016. Web.\n26 June 2017.<\/p>\n\n\n\n 5) Patel M (2017) Misconduct in Clinical\nResearch in India: Perception of Clinical Research Professional in India. J\nClin Res Bioeth 8:303. doi: 10.4172\/2155-9627.1000303<\/p>\n\n\n\n 6) Alsumidaie, Moe. “Non-Adherence: A\nDirect Influence on Clinical Trial Duration and Cost.”Pardon Our\nInterruption. Applied Clinical Trials, 24 Apr. 2017. Web. 26 June 2017.<\/p>\n\n\n\n 7) Pew Research Center. \u201cMobile Fact Sheet.\u201d\npewinternet.org\/fact-sheet\/mobile\/. Pew Research Center Internet &\nTechnology. Feb. 2018. <\/p>\n\n\n\n 8) Smith, R. J. “Adherence to\nAntiretroviral HIV Drugs: How Many Doses Can You Miss before Resistance\nEmerges?” Proceedings.\nBiological Sciences. U.S.\nNational Library of Medicine, 07 Mar. 2006. Web. 26 June 2017.<\/p>\n","protected":false},"excerpt":{"rendered":" By Takoda Roland, CCRA, CCRP Founder of Philadelphia Pharmaceutical Research Disclaimer: The examples noted in the following are all firsthand accounts of the author, but for the purpose of this article have been combined into a single site visit. The visit depicted below is an aggregate of many sites and studies and is not necessarily … <\/p>\nDay in the Life<\/strong><\/h2>\n\n\n\n
On-site<\/strong><\/h3>\n\n\n\n
The Case for Standardized Source<\/em><\/h2>\n\n\n\n
\n
The Case for Technology in Patient\nConsent<\/em><\/h2>\n\n\n\n
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The Case for BYOD<\/em><\/h2>\n\n\n\n
The Case for eSource<\/em><\/h2>\n\n\n\n