EU Recommendations on Decentralised Elements in Clinical Trials - The most important points in brief

It's here - the European Union's first guideline on digitised/decentralised studies!

Who published it?

The Accelerating Clinical Trials in the EU (ACT EU) initiative, consisting of the European Commission, the Heads of Medicines Agencies (HMA) and the European Medicines Agency (EMA)

Where does this guideline apply?

This guideline was developed for drug trials and contains some elements specific to drug trials. However, it also applies to medical device and in vitro diagnostic studies conducted in Europe.

What is it all for?

Clinical studies are going digital and we at MEDIACC see ourselves as pioneers in the digitalisation of clinical studies in Germany. While we have already implemented studies with individual digital and decentralised elements (hybrid studies) in recent years, we are currently launching the first fully digitalised clinical studies. The ACT Initiative of the European Union has now finally published its first guideline on the implementation of clinical studies with digital or decentralised elements, providing initial orientation for the implementation of modern clinical studies.

It is important to note that these are recommendations that will be updated at regular intervals. The applicable EU regulations and national provisions, in particular the EU GDPR, must be observed, which may also be stricter in individual cases.

The recommendations deal with the tasks and responsibilities of the sponsor and investigator, electronic informed consent, trial-related procedures and the administration of investigational medicinal products in the home environment, as well as data management and monitoring in the context of a decentralised clinical investigation.

As a general rule, the rights, safety, dignity and well-being of trial participants always have top priority and must not be further jeopardised by the introduction of digital elements. Any additional effort for study participants must be carefully weighed against the benefits of digitalisation.

Centralised processes at the trial centre ensure greater patient safety and are generally preferable or should be offered to trial participants in addition to the introduction of decentralised/digital elements. Exceptions are possible, but must be well justified.

How decentralised/digital elements are implemented in clinical studies always depends on the individual case and on various factors:

• Type of clinical study
• Study population, e.g. healthy adults or underage patients
• Type of indication, e.g. otherwise healthy smokers or patients with severe depression
• Type of data collection, e.g. subjective questionnaires or invasive medical examinations
• Type of product and stage of development, e.g. low (medical app) or high risk class (pacemaker)

We can remember the following: the more vulnerable the population, the less data is available on the effectiveness and safety of the product, the more complex the study concept and the associated risks, the more likely it is that decentralised elements outside the trial centre should be avoided. It always depends on the individual case and a decentralised process must be precisely described and risks for trial participants weighed up (risk-adequate approach). This applies in particular to so-called "critical-to-quality factors" (defined according to ICH E8-R1 Guideline).

The perspective of experienced healthcare professionals, investigators and patients must be obtained at an early stage - already during study planning.

A summary of the decentralised elements planned in the clinical investigation should be included in the cover letter for applications.

For studies without trial centres, i.e. without connection to usual patient care, the protection and safety of patients must be ensured (assessment of the risk profile of individual patients, including appropriate anamnestic information, physical examination and laboratory or imaging data by responsible investigators with the required specific medical background of the trial population). Exceptions must be justified in the ethics application and decided on a case-by-case basis.

The same requirements apply to the quality, validity and integrity of the data as for a traditional study. Possible challenges (e.g. increase in dropouts, lower compliance or exclusion of certain people, such as digital illiteracy) and measures to address them must be discussed in detail in advance.

The electronic collection of clinical data must take place in accordance with the guideline on computerised systems and electronic data in clinical investigations(EMA/226170/2021).

A specific contingency plan is necessary to minimise risks associated with the introduction of a digital element, e.g. failure of an appliance, unstable internet connection. This is provided by our certified information management system (ISO 27001).

Roles and responsibilities

In general, the introduction of decentralised elements can be seen as an extension of the clinical trial site to include the study participants' place of residence, which entails an additional supervisory duty for investigators and sponsors. With the introduction of decentralised elements and possibly additional service providers, alternative monitoring and control measures become necessary and the data flow and responsibility matrix become more complex. As before, responsibilities must be defined in detail and clearly in the protocol.

In particular, the responsibilities of external service providers must be clearly described, justified and contractually agreed. Responsibilities with regard to medical decisions remain with the investigator, so they must be involved at an early stage. If the sponsor selects an external service provider to take on medical care tasks, the investigator may review the contracts and ask the service provider questions to ensure that the service provider fulfils all requirements. The investigator may also make changes to the contract, reject service providers for good cause if necessary and is responsible for ensuring that the external service provider's employees have received sufficient training.

Study clarification

The use of digital tools during study information, such as electronic signatures, is possible, but should be carefully weighed against the background of the study design, the characteristics of the population (e.g. minors) and additional risks/burdens but also benefits for the study participants. In exceptional cases, the informed consent discussion may take place digitally if this can be justified accordingly. As a general rule, the higher the risk for study participants (see above), the more likely it is that the informed consent discussion should take place in person at the study centre. Study participants must always have the opportunity to have the informed consent discussion in person at the study centre with a study doctor. This may only be waived in duly justified cases.

The study information process and the methods used must be described in detail and step by step in the ethics application, which must also contain a justification for the waiver of a medical examination.

The following must be documented in the informed consent process: the receipt of the information by the study participant, possible discussion between the person qualified to obtain consent and the study participant and the granting of consent, e.g. by means of an eSignature that meets the requirements of EMA/226170/2021.

If the interview takes place completely digitally, the following applies: The informed consent discussion must take place face-to-face in real time, e.g. by video call. If the study participant is not known, the identity must be verified by the study doctor. The study participant also has the right to verify the identity of the study doctor. Deviations from this must be clearly justified in the ethics application and a description of the alternative identity verification of the study participant and physician as well as proof that the participant has correctly understood all information must be added to the ethics application in this case.

Communication channels with appropriate encryption must be used, but we already have more detailed requirements here in Germany (see Bundesmantelvertrag der Ärzte (BMV-Ä)).

During the discussion, the study personnel must pay attention to whether individual circumstances of the study participant could influence the use of digital tools in the study process, e.g. digital illiteracy.

In the case of electronic study information, consideration must be given to whether this discriminates against certain study participants, e.g. if they prefer other forms. In this case, alternative methods must be made available or, alternatively, reasons must be given as to why this is not necessary. It must be ensured that the study participant receives the study information in a form that can be stored and retrieved.

e-signature

Regardless of the format of the signature, it must be possible to reconstruct the consent process and verify the validity of the signature. The requirements of EMA/226170/2021 and national regulations apply.

According to the BfArM statement in this document, a qualified electronic signature (Regulation (EU) No. 910/2014) is required for AMG studies.

According to ISO14155, "the dated signature ... be done electronically".

When using the e-signature, study participants must have the option of downloading an electronic copy of the signed and dated declaration of consent or receiving a printout of the electronic copy. In the case of an electronic copy, it must be protected against changes; any changes must invalidate the signatures.

A process for electronic withdrawal of consent, including partial or complete withdrawal, must be defined in advance. This process should include timely notification of the investigator and a communication plan with all other parties involved. Cancellations must of course also be possible outside the system and this should be logged by the investigator.

Study procedures in the home environment of study participants

Study procedures may take place outside the study centre, e.g. at the study participant's home. They may also be carried out by study participants themselves, visiting investigators or other authorised persons. There must be no increased risk for study participants or distortion of the data and compliance must still be verifiable.

The following points must be considered and, if necessary, adapted for study procedures in a home environment:

• Suitability of the room and living situation of the study participants for the procedures (inclusion and exclusion criteria)
• Informing study participants about procedures in their home environment
• Personal and social suitability of the living situation for home visits, if applicable
• Study participants may have more than one residence
• Person carrying out the procedure is sufficiently trained/instructed and may have authorisation to carry out this procedure, e.g. taking tissue samples
• Performance of the procedure by qualified personnel can also be monitored via video telephony
• Medical activities can only be carried out by doctors
• Proper handling and storage of biological samples still guaranteed

Study participants should also be able to

• be able to visit study personnel in person if they wish
• receive assistance from study personnel for study procedures if they need it for data collection
• be provided with appliances for data collection by the sponsors if they do not wish to use their private appliances for this purpose.

Monitoring of incoming data - SAE, data management and monitoring

Study participants, investigators and service providers must be trained in the use of digital tools for data collection and, in particular, the handling of SAEs. Procedures for identifying duplicates must be developed for SAEs recorded in different ways. Data should be reviewed regularly, with the scope and frequency depending on the relevance of the data for patient safety and well-being and for demonstrating effectiveness. The strategy should also be aligned with the specifics of the study, e.g. data collection through wearables.

The establishment of notifications and alerts is recommended in order to record SAEs promptly. An assessment of the type of alerts and a description of how they should be handled and who is responsible must be part of the study protocol, especially if a digital tool generates safety-critical data that requires immediate medical attention. A schematic overview is recommended. The sponsor must ensure that the digital tools are validated and that warnings are transmitted in good time. A contingency plan (e.g. information management system (ISO 27001) must be in place in the event that a tool does not function properly, e.g. server failure of the study platform.

Study participants should be fully informed in advance about how digitally collected information will be handled. It must be made clear that the investigators cannot check this data in real time and that they must contact the investigators directly to report problems if they have any particular security concerns. All parties involved in the study should receive an overview of the data flow, ideally as a diagram with explanations.

Data collection:

• all data collection tools must be properly configured and validated
• Risk of incorrect data entry by study participants must be minimised

Data transfer:

• Use of cryptographic measures for data protection when transferring data to servers
• if source data has been deleted from its original location after it has been transferred to another location, this 2nd location must contain both the source data and its metadata

Access to data:

• Data access controlled by user rights and access procedures
• Protection against unauthorised access, e.g. through firewalls
• Principal investigators should have continuous and complete access to source data collected decentrally and in study centres as well as all source data reported to sponsors
• Remote access to medical data by monitor or auditor permitted, provided that investigators can maintain confidentiality of patient records (BfArM statement in this document)

Click here for the recommendation letter "RECOMMENDATION PAPER ON DECENTRALISED ELEMENTS IN CLINICAL TRIALS" document of the EU.

Classification of the European Union guideline on digitised/decentralised trials

Compliance with the recommendations of the EMA's "Recommendation Paper on Decentralised Elements in Clinical Trials" is crucial for the success of digital clinical studies.

These guidelines provide clear guidance on the integration of decentralised elements to ensure patient safety and data integrity. By implementing these recommendations, studies can be designed more efficiently, barriers to participation lowered and data quality improved. MEDIACC supports you in meeting these standards and successfully conducting your digital clinical studies.

(as of spring 2023)

Can we support you too? Arrange a first non-binding appointment here.