While clinical trials used to be predominantly paper-based, technology is taking over the management of clinical trial data. Nowadays we often make use of electronic patient diaries, Case Report Forms and Trial Master Files. Investigational sites have started to maintain their medical records electronically. Even the electronic Patient Informed Consent Form is on the rise.
Digitalisation has certainly introduced more efficiency and better insight into clinical trial data, but it has also brought new challenges. How do we ensure that trial data and results are and remain reliable? How do we deal with a mixture of paper and electronic records, and/or a combination of different systems? This blog gives insight in some of those challenges with references to the recently adopted ICH E6 (R2) guideline for Good Clinical Practice (GCP).
- Make sure you define the location of essential documents including source records
With the use of many different paper and electronic systems, it can be difficult to keep track on the location of study-related data. Data could be recorded and retained by different departments.
A documented overview of the location of all essential documents, including source records, can be very useful. This can be done in a list and in a visual overview of connected systems and data storage created during a data mapping assessment. The maintenance of a record of trial document location(s) is now required for Sponsors and investigational sites per revised ICH E6 (R2) (section 8.1).
- Source records should be reliable and available
A growing number of investigational sites are using electronic medical records (EMRs). There are many different systems and they are not always meeting the expectations as laid down in the GCP guideline. While ICH E6 (R2) details requirements for study and source records, it is not always easy to translate those into requirements for EMRs.
A checklist helps the monitor / investigational site to assess any site- or hospital-specific electronic systems that are used for clinical trials against GCP. This can certainly avoid issues later on. Since this evaluation is also IT-specific, a standard questionnaire could be prepared for completion by the investigator and the site’s IT department. Different health authorities, such as the European Medicines Agency (EMA) and the UK Medicines & Healthcare products Regulatory Agency (MHRA), have provided useful guidance on risks of and expectations for EMRs, which can be used as a reference.
- Investigators should have control of and access to data generated by the investigational site
Paper (copies of) completed CRFs, patient diaries and questionnaires used to be retained at the investigational site. Nowadays, most Sponsors make use of electronic versions, which are completed and retained online. In the opinion of Health Authorities, this often has resulted in Sponsors taking over control of data generated and/or reported by investigational sites or study patients.
ICH E6 (R2) (section 8.1) now includes an explicit requirement that investigators should have control of and continuous access to records generated or reported by their investigational site. This means that in the selection and set-up of clinical trial solutions, such as eCRFs and ePRO/eCOA, Sponsors should consider options to allow investigators to control their own data, e.g. by building in options to retain a local copy of the data they have submitted to the Sponsor.
- Clinical trial solutions are provided by (many) different vendors
There is a wealth of new and innovative clinical trial solutions on the market. They can build efficiency in the conduct and analysis of studies and save costs. It might be tempting to select these systems just on price and convenience. However, systems may have hidden costs. Inadequate system set-up and validation can lead to data integrity issues and unavailable systems and data.
ICH E6 (R2) 5.5.3 provides now further detailed expectations for proper handling of electronic study data and systems, which includes, system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. These processes are time- and cost-consuming and require IT specialists with GCP-specific knowledge. What is the support the vendor can provide in system validation? Which efforts should the Sponsor take before a system can be used? This should all be considered during selection of clinical trial solutions.
- All data (and metadata) should be retained, archived and available for inspection
Study record retention requirements as defined in ICH E6 (R2) 5.5.11, but also as required by EU and country-specific legislation, obviously do not only apply to paper, but also to electronic records, including metadata (e.g. audit trail or applied signatures). While storage, archiving and accessibility of data is relatively straightforward for paper records, secured storage of electronic records requires more efforts.
How (in which format?) and where are records stored? Are data stored in the cloud? Where are the data centres? What about system security? Is data (in the original format, i.e. including metadata) still accessible after a system is retired? Considerations for electronic record archiving should start at vendor selection and could finally be a reason for not selecting a particular vendor.
- Transfer of data through different systems may pose the integrity of the clinical study at risk
So far, we have considered systems as separate entities. However, this is not how it works in most clinical trials. All systems used for one clinical trial are integrated into one (trial-specific) electronic platform, in which data may be processed and transferred from one system to another. At the end of the day, all clinical trial data should end up in one clinical database. By that time these data should still be complete and fully reliable for biostatistical analysis and development of the clinical study report.
To ensure a continuously proper working electronic platform and a reliable exchange of data between the different systems, potential risks should be identified before the start of the trial. Data mapping will help you to visualise how trial data are being exchanged between systems and where potential risks or gaps exist.
Before a trial-specific platform can be used, all interfaces with the data generating and processing systems have to be tested. This should be part of the validation of the platform and the systems included. Such validation should ensure that the integrity of the data continues to be ensured, even though they have undergone processing and transfer.
This blog described six important challenges you may face with the digitalisation of clinical trials. This is not an exhaustive list of issues you may encounter in a digital clinical trial. Think of, for example, the challenges you can face with the introduction of an electronic Trial Master File or the collection (and retention) of patient data in electronic patient diaries and questionnaires (ePRO/eCOA). Though we haven’t described all of them here, we can share additional information on them upon request.
This blog made clear that the use of more and different electronic systems results in a need for additional efforts to ensure the integrity of a trial. However, digitalisation of clinical trials also introduces many opportunities. It does not only allow you to run a trial more efficiently, it also allows you to gain better insight in the data collected in a trial and as such may even increase the quality of the trial conduct, with fewer resources.
It is clear that the digital clinical trial evolution has not yet come to an end. Next to the expansion and improvement of existing electronic systems, the application of other solutions to make the execution of clinical trials more effective and efficient, such as mobile apps and wearable devices, are expected to become more present in clinical research.
Blog by: Henrieke de Bie
If you would like to learn more about this subject, have a look at a blog that focuses on data integrity and Quality Management System compliance:
Data integrity: 5 ways to be GxP compliant.