In December 2022, the EU Commission issued a recommendation paper on decentralized elements in clinical trials. This document addresses the increasing complexity in study design and development of technological tools that have led to certain trial activities and assessments being conducted outside of the clinical site, and provides guidelines for sponsors and investigators to manage these trials while safeguarding patient safety and data reliability. Particularly, this document also addresses:
An overview of national provisions regarding decentralized procedures in the different Member States is outlined in the Appendix of the Guideline.
Study oversight includes delegating study tasks, vendor quality agreements, and establishing effective lines of communication between involved parties. In decentralized trials some procedures/assessments may be conducted off-site or remotely, more vendors/service providers may be involved, or electronic tools may be used. In this scenario, Sponsor and Investigator oversight should be upheld and strengthened to ensure that subject safety and data reliability are safeguarded. To this end, written agreements shall be provided for each task that is delegated to a service provider. Additionally, vendor involvement in terms of rationale and extent of the involvement in different study tasks should be described at a high level in the protocol and in depth in a separate document to be included in the Clinical Trial application. Sponsors should ensure that vendors are qualified for the task to be performed. Moreover, effective communication plans should be in place to clearly describe information flow and this should be shared with all parties involved in the clinical study. Oversight should also be maintained regarding data being collected through different means (medical records and digital tools) and from different sources, for instance, adverse events recorded by the investigator and that are recorded by the patient in an electronic diary, to avoid duplicates.
In all cases, oversight on different study procedures should be planned before the start of the study through the implementation of different plans (for example, safety plan, monitoring plan, communication plan) defining roles and responsibilities for each task.
An important aspect of a clinical trial is that the potential trial participants give their voluntarily informed consent to participate. An informed consent process may be performed with the support of digital information leaflets and/or electronic methods for the signature of the informed consent form, however the guideline clearly states that different factors such as design of the clinical trial, the characteristics of the trial population, and the risks, burdens and potential benefits related to participating in the clinical trial must be addressed prior to implementation.
The Guidelines detail the following main aspects:
The Guideline also addresses IMP distribution to study participants. Although the decision on treatment lies within the responsibilities of the investigator, according to the Guideline dispensation and delivery of the IMP may occur directly from the clinical site pharmacy, delegated pharmacy or depot (if allowed by local regulation) to the trial participant’s home, or other address provided by the latter. Vendors who are not authorized to dispense IMPs should be at least considered qualified based on GDP by the Sponsor for this activity and agreements should be in place between all parties involved in these procedures. This process may entail an increased risk for the study participant and study data, therefore benefits for the subject should be weighed against risks of exposure to conditions that could affect product quality and integrity before off-site IMP dispensation is implemented. The possibility of implementing decentralized elements for IMP management should be considered also in light of the type of IMP used in the study and subject population, in order to avoid shipping IMP directly to the subject, for example, in case of an IMP requiring additional medical supervision.
In any case, additional oversight in terms of instructions for parties involved in the delivery, explanatory leaflets/instructions on IMP storage and administration for patients, and additional visits performed by healthcare professionals to the subjects’ home may be implemented to minimize risk for the patient.
The Sponsor should ensure that the personal data of the trial participants required for the delivery of the IMP is used in accordance with the GDPR, solely for the purpose of delivery of the IMP.
Details on IMP dispensation and delivery should be included in the IMP Dossier or other study document.
In decentralized studies, commonly different study assessments are performed at the patient’s home. The Guideline states that in this case, the patient’s home should be considered as an extension of the clinical site, meaning that standards on the quality of the data collected and study procedures should be maintained as much as possible.
The investigator should monitor compliance of the trial participant considering the lack of/decrease in the number of face-to-face visits/meetings between the trial participant and the investigator and/or delegated staff.
Additional burdens to the study subject should be avoided and the latter should be given the opportunity of visiting the study site if needed.
Decentralized clinical trials are characterized by an extensive shift of data collection from the investigator/investigator site to the trial participants and/or their caregiver and/or service providers (e.g., home nurses). Direct data capture by electronic systems (e.g. electronic Case Report Forms (CRFs), ePROs, wearables, etc.) may occur, for instance, at the clinical trial site or off-site locations.
According to ICH E6, the data recorded during the clinical trial should be credible, reliable and verifiable. In addition, the data protection requirements according to GDPR and local privacy legislation should be met.
The risk of erroneous data entry for data measured and entered directly by trial participants, especially on primary, key-secondary or safety endpoints should be minimized by appropriate measures, by means of implementation of a data flow diagram to be shared with all parties involved, by validated data acquisition and data transfer tools and by adequate protection of participants’ personal data.
As for data monitoring, the implementation of decentralized processes or electronic tools should be evaluated when defining the monitoring strategy.
This EMA recommendation paper is an important step in recognizing how decentralized trials are becoming more and more widespread not only as a response to a health emergency but in the setting of new and innovative clinical trial designs. PQE Group, with its team of highly qualified personnel, can drive Sponsors, investigators and CROs in developing and managing studies with decentralized elements by assuring the highest quality standards.
