Abstract
Abstract:
Data management is the strategy that is used for collecting, organizing, and managing data within an organization. Clinical data management plays a key part in the success of any clinical trial. The use of technology and computerized systems in the conduct of clinical trials has increased over the years and is now mainstream. The United States Food and Drug Administration has established requirements to ensure that electronic records and electronic signatures are trustworthy and reliable. Critical to the success of a data management protocol are the experienced members of the data management team. We review common aspects of data management and management systems.
Good clinical practice is an international, ethical, and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials1,2. Good clinical practice will ensure that the data and reported results are reliable and accurate and that the rights, safety, and well-being of the subjects in the trial are protected.
A fundamental basis of good clinical practice is high-quality data management, a process that is used for collecting, organizing, and managing data within an organization. Clinical data management (CDM) plays a key part in the success of any clinical trial, whether one is conducting a single-site Phase 1 trial or complex multisite Phase III trials. A superior CDM process will ensure that a high quality of data is being captured. Data quality in this instance is defined by data that are reliable, accurate, accessible, source verified in a timely manner, cost-efficient, and, most importantly, in compliance with industry and governmental regulations. Without high-quality clinical data, the value of the test product may not be fully realized1. For example, if the credibility of the data is suspect, then questions could be raised on any findings or conclusions made from the results of the trial.
The use of technology and computerized systems in the conduct of clinical trials has increased over the years and is now mainstream with all who participate in clinical trials (i.e., sponsors, clinical research organizations [CRO], and investigators). With these technological advances, the United States Food and Drug Administration (FDA) has established a code of federal regulations (CFR Title 21, Part 11). Part 11, as it is commonly known, establishes requirements to ensure that electronic records and electronic signatures are trustworthy, reliable, and are used as a substitute for paper records and handwritten signatures. Part 11 also relates directly to the way data management is performed within a clinical trial setting.
In addition to clinical monitoring and data management, quality assurance and quality control are critical for the effectiveness of a clinical trial. It is important to have minimal error in the data and no unexpected occurrences of protocol violations, in addition to ensuring that deliberate falsification does not occur (though it is believed that fraud rarely occurs)3. High-quality data management protocols and systems limit the extent to which data tampering can occur without identification.
A database is an accumulation of data for storage and future use as well as a collection of related data. A CDM system is a software system that is used to access the database. Thus, a CDM system goes beyond the function of a stand-alone database, allowing data to be captured, cleaned, and extracted from the database. There are various types of CDM systems that can be used in surgical trials, but the most common one used for single-site studies is Microsoft Access. Even though Microsoft Access is not costly to install, is easy to use, and is easily accessible on most computers, it is not a particularly powerful database and lacks the additional features of an ideal CDM system. Because of the data management process inherent in the system, the use of a CDM system can enhance the speed with which a clinical trial is conducted, making the data quickly available for review and allowing issues to be raised in a timely manner. Because of the lack of flexibility, security issues, and difficult workflow of Microsoft Access, we encourage the use of other CDM systems, including Oracle Clinical, Phase Forward InForm, Medidata Rave, or DataLabs. These are just a few examples of commercially available systems that are widely used within the clinical trial industry.
With the paper-based system, commonly known as paper case report forms (CRFs), the data are collected on site, and, subsequently, these CRFs are sent to the data management team to transfer this data to the CDM system through data entry. The data in the CDM system are then validated, and queries are raised to the clinical sites in order to clean the data.
In an electronic data capturing (EDC) system, data are collected directly into the CDM system by the investigator, who enters the patient data into an electronic CRF (eCRF) rather than onto a paper CRF. This means that data are available immediately for validation. Consequently, data management is achieved in real time, with instant edit checks/validation occurring as data are being entered into the EDC system. This results in the reduction of query time and the overall time to have clean data, compared with the paper CRF approach, where data management personnel prepare the queries to be sent to sites. With the paper approach, sites then have to prepare handwritten clarifications and send them back to the data management personnel to update within the database. This process may need to be repeated several times until all data are validated, therefore making the paper approach more cumbersome than the electronic approach. Additionally, the use of an EDC system eliminates the need for printing, binding, and shipping of paper CRFs, as well as reduces the need for storage space at a site. An EDC system also allows rapid simultaneous data visibility to investigators, monitors, data managers, statisticians, and sponsors. Finally, security measures (e.g., a password) while entering data to CRFs are not possible in a paper-based model.
While the use of eCRFs is becoming more popular, there are a few things one needs to consider before switching from paper CRFs to eCRFs. The ultimate goal for the EDC system is to speed up the process of data collecting and data cleaning, resulting in reduced time and money spent on clinical trial development. However, this does not necessarily mean that the EDC system is the best approach for a trial. The decisions on whether data will be collected via paper CRFs or EDC will depend on a number of factors, including the number of sites participating in the trial, the type of trial, the kind of data being collected, and what kinds of resources and funding are available at that time.
Oracle Clinical
One commonly used and commercially available CDM system is Oracle Clinical. It is an integrated data management system designed to reuse client or therapeutic data standards. The system allows the reduction of overall setup times and focuses on efficient study conduct. As part of its standard core functionality, Oracle Clinical allows page-level tracking of the CRFs, storage of laboratory normal reference ranges, consistent checking of clinical data through a simple programming interface, and the export of data to other formats (usually SAS datasets) in order to allow the statistical team to conduct an analysis of the data. The system has also been developed to ensure that the capture and cleaning of the data follows CFR Title 21, Part 11. Oracle Clinical has been designed to allow the easy integration of both workflow and imaging systems. It also contains an integrated HTML-based coding tool, the Thesaurus Management System, which allows the automatic and manual coding of verbatim adverse reaction and medication text in addition to promoting efficient and consistent coding. Not only does Oracle Clinical allow the use of a paper-based system, but it also has the ability to use a web-enabled architecture, which contains a fully integrated remote data capture tool, allowing for secure data entry directly from the investigator sites without the need of additional setup tasks. Table I provides a comparison between Oracle’s paper-based system and Remote Data Capture tool, which are both used in data management process tasks.
A surgical clinical trial is unique compared with the majority of clinical trials because a surgical procedure or device, rather than a drug, is being tested within a trial setting. There are noticeable differences in clinical trials evaluating drugs or surgical procedures. When a new drug is introduced, the drug itself does not change over time. Because a drug is associated with a changeable biological response, clinical trials most often require a large number of patients. In contrast, a surgical intervention changes over time as technique and experience evolve4. Additionally, surgical clinical trials are conducted in a wide variety of therapeutic areas in both adult and pediatric populations.
The design of the CRF is very important in any clinical trial and requires a complete understanding of the protocol. There are several factors that need to be considered when designing the CRF for a surgical clinical trial in comparison to a nonsurgical clinical trial. For example, in an orthopaedic surgical procedure CRF, several pieces of information may be required: (1) baseline characteristics form, (2) surgical report form, (3) follow-up report form, (4) medications form, (5) adverse event form, (6) surgical reintervention report form, (7) protocol deviations form, and (8) patient discontinuation form.
Global Adjudicator (www.globaladjudicator.ca) is a novel platform that can be used by clinical sites, administrators, and adjudication committee members. The system is FDA compliant, meeting the CFR Title 21, Part 11 criteria. The system also provides a detailed audit trail that documents important activity on the system, such as logging in, uploading materials, and deleting materials. Key features of the Global Adjudicator include the capability of collecting and storing study materials provided by the clinical sites, a viewing system where the adjudication committee members can review the adjudication materials (radiographs and clinical notes), an EDC component that allows the adjudication committee members to enter their assessments, a system that allows the compilation and review of the proposed consensus decisions, and a feature that allows the easy export of the final consensus data. This system allows single or multiple reviewers to evaluate images for outcome assessments in clinical trials (e.g., fracture healing, quality of fracture reduction, arthrodesis following spine surgery, evaluation of bone tumor size and progression, and osteoarthritis progression).
An EDC system must be able to adapt to newer versions or systems, ensuring the ability to integrate the data with in-house systems once the database has been locked. The size of the study also needs to be taken into account. For instance, certain therapeutic areas require large and complex trials that have longer study durations and more sites. Typically, in these studies, one would expect a large number of concomitant medications and adverse events. For example, an oncology clinical trial will have long-term patient follow-up and can last anywhere from five to ten years5. These studies require a single database that combines all data into a central location, which is accessible at any time or from any place during the lifetime of the study.
The cost of setting up a powerful database for a surgical trial can vary from anywhere between $5000 and $100,000. However, the benefits can outweigh the cost6, especially with the long-term effects of bringing cost-efficient improvements in the quality of data as well as reduction in database lock, resulting in an overall very efficient database7.
Critical to the success of a data management protocol are the experienced members of the data management team. These personnel perform tasks such as creating the database, creating the CRFs, data entry, data acquisition from external vendors, and reconciliation of the safety database with the clinical database. Typically, the data management plan will describe the process necessary to perform these tasks. The clinical sites are guided by the clinical research associates regarding how to execute the clinical portion of the study and collect and manage the data as indicated in the clinical monitoring plan, in addition to describing the data management plan. The CDM system would be responsible for the cleaning process of the clinical data in conjunction with others involved in the clinical trial in various areas, including clinical operations, safety, quality assurance, and study sites.
Technology is consistently becoming more advanced, and the present electronic clinical environment will likely soon become yesterday’s news. For example, Apple has already announced its ability to provide physicians and researchers the ability to access real-time data in an appropriate format at anytime with use of the iPad8. Such tablets can bring many changes to the clinical trials industry. In addition to providing researchers with quick access to patient recruitment, adverse events, and study resources, the tablets can facilitate the ordering of supplies and the signing of patient-informed consent forms, as well as give patients the ability to electronically record off-site diary data. On the medical imaging side, the tablets could be used by physicians for viewing radiographs at any location. This technology is attractive because of its low cost and ease of use9.
As the clinical trials industry is becoming more and more competitive, pressure is being applied on investigators to search for better ways to reduce the clinical trials process times and increase productivity. In order to remain competitive in today’s research marketplace, it is important to become knowledgeable about the powerful databases that are currently being used. Because of the availability of close to real-time data10, EDC systems have initiated the development of an electronic clinical environment. However, clinical trials that use paper CRFs still represent a substantial percentage of studies in many organizations11. As with all new systems, the transition will take some time to implement, and costs will increase. However, over time, the process will become familiar, costs will decrease, and more clinical trials will use the more powerful EDC systems, which ultimately will maximize the return to the organization.
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