[co-author: Alexander Wenzel]

The European Medicines Agency (EMA) has published a draft qualification Opinion[1] concerning the use of eSource Direct Data Capture (DDC) in the conduct of clinical trials in the EU. The draft Opinion was adopted by the Agency’s Committee for Medicinal Products for Human Use (CHMP). It presents CHMP’s views on the “regulatory acceptability” of eSource DDC. EMA invites the public to comment on this opinion by 14 March 2019.

The eSource DDC would be used by investigators and clinical trial staff to directly record clinical trial source data. The clinical data recorded would include electronic Case Report Forms (eCRFs) and the clinical data would be recorded using an electronic device such as a tablet. Parts of the recorded clinical data would also be made available to the sponsor of the clinical trial.

The potential advantage of eSource DDC is that it eliminates the need to capture clinical trial source data on paper or electronic media. The clinical trial data gathered would automatically be transcribed in eCRFs. The draft Opinion explains that direct data entry in the eSource DDC, would permit immediate checks of the completeness of the data entered. This would help to avoid erroneous or incomplete data entries.

The draft Opinion contains detailed technical discussion highlighting elements of the proposed eSource DDC system which would require careful consideration before the practical implementation of such system. Although it is still a draft, the Opinion may already provide useful guidance to companies considering the use of eSource DDC as to the expectations and requirements of the EMA for clinical data that is collected through eSource DDC.

It could be reasonably expected that the conduct of EMA-coordinated GCP inspections of clinical trial sites that are using an eSource DDC system would also focus on the implementation of this system. Potential concerns about the implementation of eSource DDC may have an impact on the inspections’ conclusion concerning the reliability and integrity of the clinical data.

Strict requirements for the use of eSource DDC

The draft Opinion sets out a number of requirements that would apply to eSource DDC. eSource DDC systems would be acceptable only if such systems comply with the relevant ICH Guideline on Good Clinical Practice, Regulation EU No 536/2014 (Clinical Trials Regulation) and Regulation (EU) 2016/679 (GDPR).

Another element emphasised in the draft Opinion is the requirement for eSource DDC systems to control the access of clinical trial sponsors to the recorded data. The clinical trial sponsors would have access only to pseudonymised patient data (as opposed to any data that may enable sponsors to identify individual patients). The protocol for the clinical trial should specify explicitly which parts of the pseudonymised patient data recorded through the eSource DDC, may be made available to the sponsor. Any practical implementation of eSource DDC should, therefore, reflect the clinical trial protocol and not permit sponsors to access clinical trial data which should be accessible only to the investigators and the clinical trial staff. This aspect may be particularly important if the eSource DDC database is hosted and maintained on an infrastructure that is controlled by or accessible to the clinical trial sponsor. In such circumstances, robust technical mechanisms will need to be put in place to ensure that sponsor’s access to the eSource DDC database does not go beyond what is provided in the clinical trial protocol.

eSource DDC should provide a clear audit trail of all changes made to the recorded clinical trial data. In addition, the use of eSource DDC should not impede the ability of the investigators and clinical trial staff to record clinical trial data. According to the draft Opinion, the investigators and the clinical trial staff should have, at all times, control and direct access to the data. The draft Opinion also highlights other requirements such as security, protection, encryption and availability of the data, as well as requirements for data custody and data retention.

These elements, arguably, highlight potential concerns that an incorrect implementation of eSource DDC may undermine the integrity of the recorded clinical trial data. CHMP also highlights the importance of the protection of the clinical trial patients’ rights and personal data. eSource DDC should provide effective mechanisms to ensure that the collection and processing of personal health data of the clinical trial patients complies at all times with the informed consent given by the patients and the requirements of the GDPR.

Limitations and caveats

The draft Opinion acknowledges that the application and enforcement of the Clinical Trials Regulation, as far as the authorisation and conduct of clinical trials are concerned, and the GDPR are outside the remit of the Agency. The draft Opinion does not provide any guidance on how to ensure in practice that eSource DDC implementations comply with these rules.

The draft Opinion also explicitly states that the EMA is currently developing a guidance document on Electronic Systems. Once adopted, this guidance document will be the “definitive guidance” of the EMA on this subject rather than the CHMP Opinion on eSource DDC.

It is likely that the draft for the EMA guidance on Electronic Systems will be also subject to a public consultation. The content of the guidance document on Electronic Systems and the content of the CHMP Opinion on eSource DDC would then be aligned.

What is missing in the draft Opinion

The draft Opinion does not address the use of eSource DDC for collection of clinical trial patients’ written informed consent for participation in the clinical trial. Should the clinical trial take place in a jurisdiction where patient’s explicit written informed consent is the only accepted GDPR-compliant basis for the processing of personal health data, such consent could be obtained using the eSource DDC. If applicable, explicit written informed consent regarding the potential transfer of patients’ personal health outside the EEA could also be collected through the eSource DDC.

The collection of clinical trial patients’ consents is governed by a mixture of EU-level and EU Member States national rules. The rules for example given regarding the possible legal bases for the processing of personal health data differ between the EU Member States. In some EU Member States informed consent would be the only acceptable basis for the processing of personal health data. Moreover, collecting informed consent for participation in a clinical trial through an electronic system (as opposed to consent on a paper form bearing the patient’s wet signature) may not be legally permissible in all EU Member States.

The identification of a mechanism for obtaining patients’ informed consent through the eSource DDC, while ensuring compliance with all applicable national rules in the different EU Member States, may pose a significant challenge.

[1] Qualification opinions are the outcome of a specific process established by EMA to encourage companies to seek the Agency’s advice concerning proposed innovative research methods. The draft and final opinions are made public by EMA.

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