The conduct of clinical trials still relies heavily on the use of paper documents. Of course, electronic case report forms (eCRF) have been commonly used for many years – the medical information on a patient that is transferred from the clinical trial sites (hospitals/HCPs) to the sponsor (i.e. pharma or device company) is transmitted in electronic form. The trial site’s medical information, the socalled source data is usually stored in paper and/or in electronic hospital information systems. But apart from this, the recruitment of patients, their consent process and the capture of source data is done manually – often in paper format. However, the future is likely to look different. More and more aspects of the administration and conduct of a clinical trial will be done electronically and automatically.
Some areas to further integrate digital means in interventional clinical trials for medicinal products and medical devices include (please also see the illustration below):
–– Recruiting: Patient advertising by digital means/apps provided by sponsor
–– Patient informed consent: Patient information not (only) by HCP, but by digital means/apps provided by sponsor; patient grants consent on tablet/smart phone electronically; tracking of patients’ consent process real-time electronically in system provided by sponsor
–– Tracking of patient’s medical condition between visits at site: constant monitoring of patient’s condition by wearables/digital monitoring tools and real-time capture of generated data in eCRFs
–– Patient management: Patients may receive via app medication reminders and other study related information
–– Capture of source data from visits at site: Medical information generated at the site may – upon generation – be captured by a study software provided by sponsor and is then automatically transferred into the eCRFs
The above concept of electronic management of a clinical trial and the real-time access of sponsor information on the progress of the trial and the generated medical data will most likely increase accuracy, efficiency, timing of a clinical trial and curb costs. The current technology available can implement such a concept. However, such a concept has to address several legal issues.
Of course, there are several privacy aspects to consider which are specifically related to the electronic informed privacy consent, data controlling, cybersecurity, and alike (for some of these issues, please refer to the previous article on Connecting digital tools/devices with health care professionals/organizations).
From a regulatory viewpoint, the laws of the European Member States which implement the (still applicable) Clinical Trial Directive 2001/20/EC have to be abided by. However, in the near future, the new EU Clinical Trials Regulation (EC) 536/2014 will apply – in addition to national laws still regulating ethics committee/IRB approval and further details regarding execution of the new Regulation on national level. The most important source of requirements for digital/electronic means within clinical trials is the EU/ICH GCP Guideline (CHMP, Guideline for good clinical practice E6(R2), 1 December 2016, step 5).
Like for “paper clinical trials” the EU/ICH GCP Guidelines require that clinical trials supported by digital means have to abide by the same principles. Most notably, all data collected has to be recorded, handled, and stored in such a way that ensures that it is accurately reported, interpreted and subject to verification, while protecting the confidentiality of the trial subjects.
In Section 5.5 of the EU/ICH Guidelines electronic data processing system used and provided by sponsor have to “describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use.”
This sounds doable. However, there is skepticism about the extensive use of digital/electronic tools used in clinical trials. Already back in 2010, the GCP Inspectors Working Group published a reflection paper on the use of electronic source data and data transcribed to electronic data collection tools in clinical trials (“Reflection Paper” – please also see the minutes of a joint meeting of GCP IWG and eClinical Forum (eCF) representatives on electronic data capture systems and investigator site eSource readiness of 11 June 2013). These documents and our experience with competent authorities, GCP inspectors and representative in ethics committees/IRBs show that the bars for extensive use of digital means in clinical trials are high.
The most important legal/GCP issues to address when introducing digital tools/systems in a clinical trial are:
Patient advertising by digital means/apps is considered in line with the law. However, competent authorities (including GCP inspectors) consider the recruiting of patients as a responsibility of investigators (HCPs). Thus, in their view, sponsors may support – also with digital tools the patient recruiting, but the ultimate control would need to remain still in the investigators. The set-up of digital tools need to adhere to this sufficiently.
Patient informed consent
Currently, most authorities consider the information collected in a face-to-face setting as a crucial part of the informed consent procedure. Informing the patient via digital tools before the patient grants consent may – in the view of many authorities – be only supported by digital tools, such as informational apps, videos and the like – but may not replace the face-to-face meeting. Remote informing via the internet (i.e., Skype) seems to become more acceptable to authorities in some Member States, but is still seen as skeptical.
Collecting patient consent by electronic signature may arguably be feasible under the Eidas Regulation (EU) No 910/2014 on electronic identification and trust services for electronic transactions. However, national pharma laws still may require wet- ink signature of clinical trial subjects. Also, the view of authorities is quite restrictive when it comes to electronic signatures by which a patient grants consent.
The laws and authorities are less strict with regard to sponsors tracking and following-up on the progress of patients’ informing and consenting.
Tracking of the patient’s condition between visits at site via digital monitoring tools
The constant monitoring of the patient’s medical condition by wearables/digital monitoring tools is widely accepted. Of course the monitoring tools would need to be validated and – since they are mostly medical devices – CE marked. This is due to authorities and ethics committees not accepting the use of monitoring devices in clinical trials if such use adds another layer of uncertainty on the generated data. Also patient management (application/medication apps, reminders etc.) are in line with GCP requirements and admissible.
Capture of source data from digital/remote patient monitoring and generated in site visits
Medical information about the patient which is generated within the clinical trial is considered socalled source data. EU/ICH GCP guideline requires that source data is stored at the investigator/ trial site. Authorities want to be able to find source data at the site for inspection and verification. Traditionally, source data is contained in the patient file at the site in physical or electronic form. A concept where the data capture of patient data initially happens in an electronic system which is provided and hosted by the sponsor and where such data is automatically transferred in eCRF or actually is the eCRF has to address certain GCP requirements. In our experience, such a concept still has to overcome several conventional expectations on handling of source data and CRF data.
Major aspects to address are:
–– Precise description of data entry, data capture, data flow, transcription of data, and exporting
–– Demarcation and definition of source data and CRF data and its respective physical/electronic location at any point in time
–– Audit trail for each piece of data – similar or better than data on paper
–– Investigators’/sites’ control and access over source data – opposed to CRF data
–– Provision of electronic system for data capture by sponsor and ultimate user/admin rights of sponsor and its required limitations
–– Validation and qualification of such electronic system by investigator/site?
–– Clear demarcation of responsibility of sponsor, site, and investigator according to GCP
–– Continuous access provided to relevant involved parties as required by GCP retention periods – also considering technical disruptions
–– Needs and requirements of investigators and site to keep medical records under local laws and for defense purposes.
In our view, there are technical solutions and legal remedies for the above selection of the most important issues. The more the use, reliability, and confidence in digital tools and electronic data management systems increases, such tools and systems will be further introduced into clinical trials – and will be also accepted by competent authorities. To date, the setting-up and use of such tools requires meticulous diligence and also some legal arguments towards authorities.