Volume 7 Issue 560 Journal for Clinical Studies

EDC and Risk-based Monitoring

Today we are flooded with data, and managing that data in an efficient, accurate, and timely way to find and limit risk is crucial. How do we make sense of it all and use it to minimise clinical trial risk as much as possible?

Electronic data capture (EDC) is evolving as a critical element of risk-based monitoring (RBM). RBM, which replaces the more traditional one-size-fits-all-approach to site monitoring, is a more proactive approach in that it tackles issues with the study based on key performance indicators and assigns resources where they are required most, thus increasing overall efficiency. EDC systems have an increasingly critical role in the execution of clinical trials by optimising subject tracking, enrolment, visits, drug distribution, safety issues and dropout rates. Although RBM has strengthened our ability to manage risk, there’s another big factor. In order to provide risks metrics, integration is required between the system tracking the study design, monitoring activities/milestones, and the EDC system.

What if there are changes midway through the study? Assessments can be made during the course of the study to weigh the impact of changes due to protocol amendments, issues, staff changes, SAEs (serious adverse events) and SUSARS (suspected unexpected serious adverse reactions), screen failure rate, subject withdrawal rate and data issues. How do you monitor how much risk each site is taking? Overall risk averages should be done in order to determine the initial monitoring activities for each site. As the study progresses and risk either increases or decreases, the project manager and clinical study monitors can leverage the EDC system to make informed decisions on where to exactly focus monitoring activities.

EDC RoleCollecting large numbers of variables, combined with a large number of subjects to be followed, is an extremely challenging part of subject tracking. According to the textbook Practical Guide to Clinical Data Management, “If subject enrolment was climbing to the end of the study, there will be a large influx of new data and new queries as the study ends. If enrolment was tapering off and only a few subjects are still outstanding, the effort for monitoring and data entry (for site or sponsors) is obviously much less.”1

In order to determine how subject data is to be analysed and collected, instruction for sites and monitors also needs to be pinned down and represented by all groups. Also factored in is the clinical trial strategy and viable EDC component of drug distribution and reduction in clinical costs.

Analyzing Risk in a Clinical TrialLennart Sjöberg et al. found “everyone is seeking to manage risk, and they are all guessing because if they knew for certain, they would not be dealing with risk.”2

If only analysing risk was as easy as looking it up in a book. Unfortunately analysing risks in a clinical trial is not an exact science. Assessments can be performed during the initiation phase of the trial to determine the risks by region, study

design complexity, site experience, product safety, treatment procedure and study patient population. These are called static risks. What if there are changes due to factors such as protocol amendments, issues, staff changes, SAEs and SUSARS, screen failure rate, subject withdrawal rate and data issues? Assessments can be continuously made during the course of the study to weigh the impact of these changes, as well. These are called dynamic risks.

The overall risks that affect the rate of monitoring activities would be the weighted average of both the static risks and the dynamic risks.

More efficient and effective protocol design, reduction in costs, and the ability to strategically adjust oversight in keeping with changes in risk level are all part of the RBM framework. But it’s not all gloom and doom. With early planning, analytical expertise, sophisticated tools and process adaptability, realising the potential of RBM can be achieved according to Alexander Artyomenko, MD, PhD, Global Director, Medpace Late Phase Clinical Operations. “Deep cross-functional expertise early in the trial process enhances the ability to assess overall risk, define critical data and processes, develop an integrated plan for addressing risk, and execute a monitoring plan that meets the trial’s unique requirements,” he notes.3

Figure 1. Model Approach for RBM Monitoring5

The Importance of Linking EDC and RBMAccording to Wikipedia4, “EDC is a computerised system designed for the collection of clinical data in electronic format for use mainly in human clinical trials.” And it provides many benefits. Expediting the time to market for drugs and medical devices is all part of the EDC solution and replaces the traditional paper-based data collection methodology. Many people, companies, and clinical research organisations in the industry have accepted this EDC solution. So what else does this system provide? Well, to begin with, it’s a graphical user interface component for data entry. You can also use it as a reporting tool for analysis of collected data. In addition, you can also use it as

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a validation component to check user data.

How Does an EDC System Relate to Tracing Overall Risks and Intelligent RBM?In order to provide overall risks metrics, we need true integration between the EDC system and the clinical trial management system (CTMS), or to be more specific, the system tracking the study design, monitoring activities, milestones and the system tracking subject enrolment, drug distribution, SAEs and issues. A weighted overall risk average should be assigned to each clinical site in order to determine the initial monitoring activities for each site. As the study progresses and dynamic risk increases or decreases based on real-time metrics, the project manager and clinical study monitors should be aware of these changes and should be given the tools to adjust monitoring activities accordingly.

Patient safety programmes require meaningful metrics and must be able to measure, identify, eliminate errors, and limit injuries. By integrating a valid and reliable framework of available metrics, we can improve initiatives, and enhance transparency by public reporting, organisation accreditation and even contracting and reimbursement. According to the article “Risk-Based Approaches” 6: “RBM includes centralised and on-site monitoring of source records, which are two complementary activities that ensure data quality and integrity. Overall, centralised and risk-based data monitoring activities need to:

• Increase quality (clearly identify and address risks)• Ensure data origin, validity, quality, and accuracy• Be verifiable, reproducible, and documented• Be risk-based and reactive• Be as easy as possible to implement• Allow/support fraud detection• Ensure ease of internal/external inspection of the source

(sponsor audit/regulatory inspection)• Be more efficient (better use of resources)”

In relation to study design, metrics can be valuable indicators of unhealthy code design, pointing out areas where problems are likely to occur by focusing on specific quality attributes. Study design can take these into account and mitigate risks and issues that may arise in development and study build. But that’s not all EDC can offer. Along with special milestones and system tracking, an EDC system can provide planning, readiness, performance, and reporting of clinical trials, with an emphasis on keeping up-to-date contact information for participants and tracking deadlines for those regulatory approval or issue progress reports. A RBM system or CTMS, according to Beth Harper, President of Clinical Performance Partners, can address “inefficiencies inherent in the operational side of research, including site performance tracking and management, patient recruitment, team collaboration, resource management, supply chain management, and regulatory document management.” 7

Impact of Protocol Amendments: According to the CFR 21 Part 11 3.1.2, “if there are any changes in the protocol due to an increase in drug dosage or duration, increase in the planned number of subjects enrolled, or new or dropped test procedures, then a summary description of the changes must also be submitted to the FDA (or relevant health

authority).” 8 So this addresses amendments, but what about other RBM issues? Both EDC and RBM must take into account the following:

• Assessment of recruitment and registration of sites• Conduct on-site education or CBT (computer-based

training)• Confirm timelines and quality of data entry• Essential documents review• Monitor and delegate responsibilities• Query resolution review• Protocol compliance in regard to the CRF (case report form)• Verify site’s completion of previously identified actions

Based on the paper, “Model Approach for Risk-Based Monitoring,” “As each task is addressed and completed above, the study team must be able to assess or rank the risk, eliminate the occurrence, or if that is not possible, manage the risk to minimise its impact.”6

Figure 2. Model Approach for Risk-based Monitoring5

Impact of SAEs and SUSARs on EDC and RBMDue to the risk associated with a clinical trial and the nature of the study, it is appropriate and reasonable to collect SAEs and SUSARs. According to a leading EDC solutions provider, “Using EDC as the single place for investigational sites to report SAEs offers sponsors a multitude of benefits. Besides minimising reconciliation across multiple safety data sources and eliminating the burden of a redundant and laborious paper process, using EDC for SAE reporting simplifies life for site staff, who will now only need to interface with one electronic system, rather than several.”9

SUSARs, on the other hand, should be reported to the manufacturer indefinitely by the investigator to the sponsor after the patient has completed the clinical trial. One has to understand the special requirements needed when processing SAEs and SUSARs. Some key differentiators include data entry and updates that require immediate attention with respect to electronic SAE pages in an EDC system. The drug safety team has to also play an integral part of the query-management process.

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Volume 7 Issue 562 Journal for Clinical Studies

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Finally, from an EDC perspective, you have to remember that most of the data on SAE pages already exists on other pages within the database.

Meyer et al. state, “EDC systems coexist with legacy drug safety applications and paper- or fax-based SAE processes. A state-of-the-art EDC solution should provide features that support electronic SAE handling within the EDC system. Designing smart eCRF pages, along with making full use of its capabilities will significantly enhance data quality and the effectiveness of the SAE process when choosing the right EDC solution.”9 In short, EDC is the repository for AEs, SAEs and SUSARS that occur in the study. These safety events are among the main indicators of dynamic risks and thus, overall risk affecting your study.

What About EDC and RBM Assessments Made with Respect to Screen Failure Rates? Elm, JJ et al. state, “Clinical trials frequently spend considerable effort to collect data on patients who were assessed for eligibility but not enrolled. The Consolidated Standards of Reporting Trials (CONSORT) guidelines’ recommended flow diagram for randomised clinical trials reinforces the belief that the collection of screening data is a necessary and worthwhile endeavour.” 10 What the investigator or potential sponsor has to take into account when collecting data is, does it contain enough scientific, trial management, and ethno-socio-cultural information? Due to the variation in site procedures, multicenter trials face obstacles in collecting data completely and uniformly, in spite of attempts to standardise the collection of screening data.

Elm goes on to say, “In spite of attempts to standardise the collection of screening data, due to differences in site processes, multicenter clinical trials face challenges in collecting those data completely and uniformly.”10 Selection bias and the ability to assess generalisability of meaningful characteristics of subjects

must also be taken into account when looking across studies.

What About Subject Withdrawals in Regard to RBM and EDC?According to Guidance for Sponsors, Clinical Investigators, and IRBs: Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials, “When a subject chooses to withdraw from (i.e., discontinue his or her participation in) an ongoing research study, or when an investigator terminates a subject’s participation in such a research study without regard to the subject’s consent, the investigator may retain and analyse already collected data relating to that subject, even if that data includes identifiable private information about the subject.” 11

It’s costly to have a subject leave a study. To a research company, under-enrolment and high dropout usually mean delays, and delays mean additional costs and loss of revenues. So an intelligent approach to monitoring that takes into account screen failure rates and increases monitoring activities to help decrease these rates can offer exciting potential to return on research and development investments.

Finally, How Does Risk-Based Monitoring Address Data Issues?Data quality assessment is the process of exposing technical and business data issues in order to plan data cleansing and data enrichment strategies. Technical quality issues are generally easy to discover and correct, such as:

• Inconsistent standards in structure, format/values• Missing data, default values• Spelling errors, data in wrong fields

Data quality is another crucial element of risk monitoring. Assessments recognise data quality problems, including metadata issues, so they can be accurate. In other words, the problems can’t be fixed until they are identified, and assessments

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can pinpoint these data quality problems and issues. By analysing EDC clinical data and applying RBM on actions taken or recommended, and by addressing non-compliance, data irregularities, and other deficiencies, we can limit data issues and keep track of who conducted the monitoring and the date. Along with focusing on critical data integrity issues, RBM will ensure that there is constant communications with the sites that require more guidance, thus decreasing delays, ensuring compliance, and lowering costs.

Conclusion Because of the challenges in RBM, the clinical research industry has had to basically shift its overall thinking regarding EDC. Since the inception of the use of EDC and the processes and tools that we employ for ensuring compliance of clinical trial data, the effectiveness, efficiency, and monitoring process have not been able to completely benefit from technology’s advancement. Risk-based approaches to clinical trial monitoring have provided very useful details about the elements of EDC. With the ability to leverage the information gathered via EDC to create a more proactive approach to monitoring, it is time to move away from the one-size-fits-all-approach to monitoring.Healthcare companies can work towards more opportunities and incentives to stimulate industry experts to support and adopt RBM processes that enhance data quality, and dramatically reduce costs. It’s necessary to bear in mind that to gain the most benefit, we must be active in following through on our plans. We must remember that this awareness bears no value in and of itself, without the ability to deal with the results. When a red flag is raised due to the organisation’s risk assessment, we must be able to implement our plans immediately and without delay.

Transparency is essential, and study protocols must furnish adequate and sufficient detail in how they will ensure the quality of data and integrity throughout the trial. We will have to conquer the natural apprehension and move out from our comfort zones, to achieve the kind of quantum leaps needed.With the industry moving forward and the recent guidance documents reflecting this direction, we can take some sort of comfort knowing that RBM is here to stay, and the correct EDC solution that helps us track overall risk is key.

References1. Prokscha, S. (2012). Practical Guide to Clinical Data

Management, Third Edition, 13, 130. Available at http://www.amazon.com/Practical-Guide-Clinical-Management-Edition/dp/1439848297. Accessed August 15th, 2015.

2. Lennart, S., Bjorg-Elin, M., & Torbjorn, R. (2004). Explaining Risk Perception. An evaluation of the psychometric paradigm in risk perception, 1, 7. Available at http://www.svt.ntnu.no/psy/torbjorn.rundmo/psychometric_paradigm.pdf. Accessed August 15th, 2015.

3. Artyomenko, A. A. (2014). The Role of the CRO in Effective Risk-Based Monitoring, MEDPACE, 1. Available at http://www.medpace.com/Offers/RBM/Risk-Based-Monitoring-Medpace-Whitepaper.pdf. Accessed August 15th, 2015

4. Electronic Data Capture. Retrieved July 28th, 2015, from the EDC Wiki: https://en.wikipedia.org/wiki/Electronic_data_capture

5. TransCelerate Biopharma, Model Approach for Risk-

Based Monitoring, page 23 (2013). Available at http://www.transceleratebiopharmainc.com/wp-content/uploads/2013/10/TransCelerate-RBM-Training-Participant-Guide.pdf. Accessed August 11th, 2015.

6. Risk-Based Approaches, Applied Clinical Trials, August 1, 2013. Available at http://www.appliedclinicaltrialsonline.com/risk-based-approaches. Accessed August 11th, 2015

7. Harper, B., Meshing EDC with CTMS, Bio-IT World (2007). Available at http://www.bio-itworld.com/issues/2007/feb/cover-story/. Accessed August 11th, 2015.

8. Code of Federal Regulations Title 21, US Food and Drug Administration (2014). Available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed August 11th, 2015.

9. Knoesel, J., Meyer, D., Lux, H. SAE Reporting in EDC Trials, Applied Clinical Trials (2008). Available at http://www.appliedclinicaltrialsonline.com/sae-reporting-edc-trials. Accessed August 11th, 2015

10. Elm, J.J., Palesch, Y., Easton, J.D., Lindblad, A., Barsan, W., Silbergleit, R., Conwit, R., Dillon, C., Farrant, M., Battenhouse, H., Perlmutter, A., Johnston S.C. US National Library of Medicine, National Institutes of Health, Pubmed, Screen failure data in clinical trials: Are screening logs worth it? Clin Trials August 2014 11: 467-472, first published on June 12, 2014. Available at http://www.ncbi.nlm.nih.gov/pubmed/24925082. Accessed August 11th, 2015

11. U.S. Department of Health and Human Services Food and Drug Administration Guidance for Sponsors, Clinical Investigators, and IRBs, “Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials (2008). Available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126489.pdf. Accessed August 11th, 2015

Richard Garcia has over 15 years of experience supporting oncological, neurological, endocrine, cardiovascular, and musculoskeletal clinical research activities through careful analysis, review and application of industry standard practices, policies and procedures. Richard graduated with honours from St Edwards’s University in Austin, Texas and has

worked for numerous CROs and pharmas such as INC Research, Pharmanet, GSK and UCB.Email: rgarcia@arisglobal.com

David Lopez offers more than 15 years of experience in the clinical research and pharmaceutical industry. His proven experience leading global projects in blue-chip companies and services has been with a focus on change management, application technology training, and regulatory compliance. David has supported clinical research client groups in over

60 countries and four continents and he has been responsible for supporting pre-sales and change management activities for ArisGlobal’s clinical product suite. He holds a business degree from Rutgers University and currently lives in London.Email: dlopez@arisglobal.com

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