EU recommendations on decentralized elements in clinical trials - The most important points in brief

It's here - the first European Union guideline on digitized/decentralized studies!

Click here for the EU document.

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 studies and contains some elements specific to drug studies. However, it also applies to medical device and in vitro diagnostic studies conducted in Europe.

What's it all for?

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

Important: These are recommendations that are to 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 address the roles and responsibilities of sponsor and investigator:in, electronic informed consent, trial-related procedures and administration of investigational drugs in the home setting, and data management and monitoring in the context of a decentralized clinical trial.

In general: The rights, safety, dignity and well-being of the study participants always have top priority and must not be additionally jeopardized by the introduction of digital elements. Any additional effort for the study participants must be carefully weighed against the benefits of digitization.

Centralized processes in the trial center ensure greater patient safety and are generally preferable or should be offered additionally to trial participants when decentralized/digital elements are introduced. Exceptions are possible, but must be well justified.

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

• Clinical trial type
• 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 available on efficacy and safety of the product, the more complex the study design and the risks involved, the more likely it is that decentralized elements outside the trial site should be avoided. It always depends on the individual case and a decentralized process must be precisely described and risks for study 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 and investigators as well as patients must be obtained at an early stage - already during study planning.

A summary of the decentralized elements planned in the clinical trial should be included in the cover letters of applications.

For studies without investigational sites, i.e., without connection to usual patient care, patient protection and safety must be ensured (assessment of the risk profile of individual patients, including appropriate medical history information, physical examination, and laboratory or imaging data by responsible investigators with the required specific medical background of the study 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. Potential challenges (e.g., increase in dropouts, lower compliance, or exclusion of certain people, such as digital illiterates) and measures to address them must be discussed in detail in advance.

Electronic collection of clinical data must be in accordance with the Guideline on Computerized Systems and Electronic Data in Clinical Trials(EMA/226170/2021).

A specific emergency plan is necessary to minimize risks associated with the introduction of a digital element, e.g. failure of a device, unstable Internet connection. This is provided by our certified information management system (ISO 27001).

Roles and responsibilities

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

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

Study Clarification

The use of digital tools during informed consent, such as electronic signatures, is possible, but should be carefully considered 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 interview may take place digitally if this can be justified accordingly. In general, the higher the risk for study participants (see above), the more likely it is that the information session will take place in person at the study center. Study participants must always have the opportunity to have the informed consent discussion personally on site with a study physician. Only in duly justified cases may this be waived.

The study elucidation process and the methods used must be described in detail and step-by-step in the ethics application, which must also include a justification for waiving a medical examination.

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

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

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

During the interview, study personnel must be alert 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, it must be considered 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 according to EMA/226170/2021 and national regulations apply.

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

When using e-signature, study participants:in must be able to download an electronic copy of the signed and dated consent form or receive a printout of the electronic copy. In the case of an electronic copy, it must be protected from changes; any changes must invalidate the signatures.

A process for electronic revocation of consent, including partial or complete revocation, must be defined in advance. This process shall include timely notification of the investigator and a communication plan with all other parties involved. Revocations 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 center, e.g. at the home of the study participant. They may also be performed by the study participant him/herself, by visiting investigators or by persons otherwise contracted. There must be no increased risk for study participants or distortion of the data, and compliance must remain verifiable.

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

• Suitability of the premises and living situation of the study participants:in for the procedures (inclusion and exclusion criteria).
• Educating study participants:in about procedures in their home environment.
• Personal and social suitability of the housing situation for home visits, if applicable.
• Study participants:inside could have more than one residence
• Person performing procedure sufficiently trained/instructed and, if applicable, has permission to perform this procedure, e.g. taking tissue samples
• Performance of the procedure by qualified personnel can also be monitored via video telephony
• medical activities can be performed only by doctors
• Proper handling and storage of biological samples continues to be ensured

Study participants should also

• Be able to see study personnel in person if they so desire
• Be able to receive assistance from study staff for study procedures if they need it for data collection
• Have devices provided for data collection by sponsors if they do not want to use their personal devices for this purpose.

Monitoring 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 differently recorded SAEs. Data review should take place regularly, with scope and frequency dependent on the relevance of the data to patient safety and well-being and to evidence of effectiveness. The strategy should also be guided by specifics of the study, e.g., data collection through wearables.

The establishment of notifications and alerts is recommended to capture SAEs in a timely manner. An estimate of the type of alerts, as well as 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 require immediate medical attention. A schematic overview is recommended for this purpose. The sponsor must ensure that digital tools are validated and that warnings are transmitted in a timely manner. A contingency plan (e.g., information management system (ISO 27001) must be in place in case 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 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 means shall be properly configured and validated
• Risk of incorrect data entry by study participants must be minimized

Data transfer:

• Use of cryptographic measures for data protection during data transfer to server
• if source data has been deleted from its original location after being transferred to another location, this 2nd location must contain both the source data and its metadata

Accesses to data:

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