7. Decentralized Clinical Trials

7.1 Do the country regulations allow Decentralized Clinical Trials (DCT) elements (e.g., eConsent, ePRO administration, remote investigator site, etc.)?

Yes.

7.2 Is there any specific regulation/ guidance on the use of DCT elements within a clinical trial?

Yes, within the European Union, the EMA published a “Recommendation Paper on Decentralized Elements in Clinical Trials” in Dec 2022.

The German authorities have not published any additional or complementary opinion on decentralized clinical trials yet.

7.3 What is the overall acceptability of DCT elements by the German Regulatory Authorities and Ethics Committees?

Overall, DCT elements are accepted but it is important that the sponsor takes into consideration the recommendations provided by the EMA. 

Additionally, requirements can also be discussed with BfARM and/or PEI for study-specific trials.

7.4 Has a fully virtual trial (DCT) been conducted in the country yet? If so, please provide an example including the registration number and any link to it, whether COVID/non-COVID trials.

Yes, at least one clinical trial has been approved with a fully decentralized arm and is currently recruiting in Germany. This study can be found on the CTIS portal with reference number 2022-500449-26-00 organized by Trials@Home.

7.5 Are there any non-regulatory DCT initiatives in the country, such as where the investigator sites and local CROs founded an alliance?

Yes. In the past, BVMA, the German Federal Association of Contract Research Organizations, has been discussing DCT initiatives within their annual symposiums, where the German pharmaceutical industry, investigators, site representatives as well as representatives from the regulatory authorities took part.

7.6 Are there any general considerations when using DCT elements in a study?

Sponsors must make sure that the study design and the DCT elements are fit for purpose, taking into consideration the intended population and the safety profile of the study drug, and ensuring appropriate risk management is applied.

Sponsors must provide to the authorities clarity, risks and benefits of using DCT elements in a study, demonstrating how participant safety (data and physical) and well-being are guaranteed, how GCP standards will be upheld, and how compliance with data privacy requirements (GDPR and the German Federal Data Protection Act) will be maintained. 

When considering a DCT/hybrid study, it must be ensured that the sponsor and investigator are able to keep oversight of trial participant safety and well-being.

Oversight: 

• Providing clear roles and responsibilities.
• Documenting which tasks are conducted: where, when, and by whom and how oversight is maintained.
• Clear communication plan between the different parties involved: sponsor, investigator, participants, and service providers.
• Trial participants were informed on information flow, and how to make contact to acute safety concerns/events, device malfunctions, and other questions.
• Training of participants and study staff in the use of any electronic platforms or devices to be used within the study.

It is important to conduct a trial-specific risk-benefit assessment when proposing a decentralized clinical trial (DCT). This assessment evaluates whether the proposed elements are suitable for the participant populations involved in the trial. Regulators typically expect this assessment to ensure participant’s safety and data integrity.

It is advisable for sponsors wishing to use decentralized elements in a clinical trial to discuss prior with the applicable German Regulatory Authority (BfArM or PEI).

7.7 Considerations/Requirements for the Use of eConsent/Remote Consent

eConsent and remote consenting are permitted in Germany.        

BfArM's response included under the “National provisions” appendix within the EMA's “Recommendation paper on Decentralized Elements in clinical trials” on question 11: Is a physical face-to-face meeting between the trial participant and the PI or a member of the research team always mandatory during the consent procedure (even if the rest is conducted remotely)?

Response: “Face-to-face meeting not subject to German Medicinal Product Act. According to Model Professional Code for Physicians of the German Medical Association, exclusive counselling or treatment via communication media is permitted in individual cases if this is justifiable from a medical point of view and the required medical care is observed, in particular by the way in which the findings are ascertained, counselling, treatment and documentation are carried out and the patient is also informed about the special features of exclusive counselling and treatment via communication media.”

Additionally, in 2021, an event (Dialog Event) was organized by BfArM, where DCT elements were discussed, and some considerations given:

- A trial site remains responsible for ensuring that the study participant understands the content of an Informed Consent Form (“ICF”). 

- The ICF is made available to the study participant, who is given sufficient time to read it and is able to ask the investigator related questions.

- The ICF is personally dated and signed by the participant (or their legal representative) and by the investigator.

- In a DCT, the ICF could be displayed to the patient on a digital device and may incorporate multimedia. Consideration needs to be given to access by the patient to a private location while accessing the ICF, whether eConsent may be provided by the patient while using their own device, whether WiFi access is required to be provided for the patient, automatic version control of software used, and monitoring of any re-consents.

7.8 Considerations/Requirements for the Use of eSignatures

BfArM's response included under the “National provisions” appendix within the EMA's “Recommendation paper on Decentralized Elements in clinical trials” on question 12: Is it possible to use electronic signatures instead of wet ink? If yes, please specify in the footnotes which eIDAS category is expected for the electronic signature.

Response: “Only possible, when qualified electronical signature (eIDAS).”

7.9 Considerations/Requirements for Electronic Patient Reported Outcome (ePRO)

This is not specifically addressed in the national legislation; however, German CAs and ECs accept the use of ePROs within clinical trials.

The EMA “Recommendation paper on decentralized elements in clinical trials” makes some remarks with regard to ePROs:

The trial participant should be fully informed in advance on how the information transmitted via digital tools, for example electronic Patient Reported Outcomes (ePROs), will be acted upon. It should be made clear to the trial participant that the investigator may not review such data in real time, and that if the trial participant experiences any specific safety concern they need to directly contact the investigator to report such an issue.

ePROs considerations are also reflected within the EMA guidance on “Computerized Systems and electronic data in clinical trials.”

7.10 Considerations/Requirements for Home Health Care (HHC)- Home Nursing

Home nursing is permitted in Germany. However, the sponsor must make sure that the use of HHCP in a clinical trial follows the recommendation provided by the EMA in their “Recommendation paper on decentralized elements in clinical trials”. 

EMA's summary of these recommendations can be found below: 

• Investigator to ascertain suitability for trial procedures to be conducted at the participant’s home.
• Inclusion/exclusion criteria should include provisions related to adequacy of participant’s home.
• Participant should be informed during the consent process about planned trial procedures conducted at their home.
• Trial-related procedures at home should only be done if the procedures do not cause additional risk to trial participant or reliability of the data and the person performing the task is qualified and/or trained to perform the task. 
• The sponsor and/or investigator should ensure that appropriate guidance and training are provided to the delegated person(s) to conduct the tasks at home correctly. 
• The insurance or indemnity or a guarantee or a similar arrangement foreseen by CTR or the CTD should be in place to cover any damage resulting from trial-related procedures performed at home. 
• 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. 
• Trial participants should be given the opportunity to visit the investigator in person if needed/preferred and they should be able to have a direct contact line if further support to perform a trial-related task/collect data is needed. 
• There should be procedures in place for reporting and management of adverse events noticed by the trial participant or by any delegated person during home visits.
• The sponsor should provide alternatives if a trial participant is unable or not willing to use her/his/their own private device (mobile phone, tablet, etc.) to capture trial data. 

Qualification on the HHC will also depend on the type of responsibilities allocated to the individual HHC.

7.11 Considerations/Requirements for HHC - Home Lab Collection

In Germany, it is permitted to collect biological samples from study participants. However, the sponsor should take into consideration EMA’s “Recommendation paper on decentralized elements in clinical trials”. 

Collection of biological samples at home is permitted, as long as the procedures involved do not cause any additional risk to trial participants or to the reliability of the data, and the person performing the task is qualified and/or trained to perform the task. If biological samples are collected at home, it should be considered whether persons taking the sample are qualified and allowed by their local legislation to take the sample. In addition, adequate handling and storage conditions for the samples throughout the entire process should be assured.

There may be additional requirements at the country level, such as IATA training for handling infections and biological material.

7.12 Considerations/Requirements for Direct-to-Patient Study Product Delivery

According to the response provided by BfArM within the Appendix “National Provisions Overview” of the EMA's Recommendation paper on decentralized elements in clinical trials, delivering or dispensing investigational medicinal products to participants is permitted.

See below the questions and answers provided by BfArM.

Q1: Is it possible to deliver IMPs directly to trial participants from their associated trial site?

Response: Yes*. *Not subject to CT legislation.

Q2: Is it possible to deliver IMPs directly to trial participants from the pharmacy associated with the trial site?

Response: Yes*. *Certain restrictions (e.g.: hospital pharmacies) may apply.

Q3: Is it possible to deliver IMPs directly to trial participants from any delegated pharmacy?

Response: Yes.

Q4: Is it possible to deliver IMPs directly to trial participants from the IMP manufacturer with an MIA license?

Response: No. In principle: Not allowed. According to Section 47 (1) sentence 1 number 2 letter g German Medicinal Product Act, pharmaceutical entrepreneurs and wholesalers may only supply pharmacy only medicinal products only then directly and only to hospitals and doctors if the medicinal products are labeled "Intended for clinical trials", provided they are supplied free of charge. 

Exceptions: According to an exemption valid until 31. December 2023, the NCA may, by way of derogation from Section 47 (1) sentence 1 number 2 letter g AMG, permit pharmaceutical entrepreneurs (also: sponsors) and wholesalers to make medicinal products labeled for clinical trials available free of charge to participants in a clinical trial if, after an assessment to be carried out by the sponsor on a case-by-case basis, the safety of the persons participating in the clinical trial and the validity of the data collected in the clinical trial are guaranteed and the pseudonymization of the data is ensured by appropriate measures that the trial participants have the right to contact the sponsor.

Q5: Is it possible to deliver IMPs directly to trial participants from the trial sponsor (sponsors intermediaries/depots)? If yes, the footnote states if a license is required for the depot to carry out this task and how to obtain this license.

Response: No.

Q6: Is it possible to deliver IMPs directly to trial participants from e.g. distribution/manufacturing/pharmacy license holders located in other EU MSs if legally allowed to carry out this task in the country of origin?

Response: No*, see also explanation under Q4.

Q7: Is it possible to deliver IMPs directly to investigators from e.g. distribution/manufacturing/pharmacy license holders located in other EU MSs if legally allowed to carry out this task in the country of origin?

Response: Yes*. *Section 47 (1) sentence 1 number 2 letter g and section 73 (2) number 2 German Medicinal Product Act.

Q8: Is it possible for any delegated pharmacy to label IMP or is this restricted to the pharmacy associated with the trial site?

Response: *, it is crucial, that the manufacturer of the pharmacy has a manufacturing license.

Q9: Is it possible to deliver or dispense authorized IMPs directly to trial participants from pharmacies not associated with the clinical trial sites? This includes authorized investigational medicinal products not used according to their SmPC.

Response: Yes.

Q10: Is it possible to deliver or dispense non-authorized IMPs directly to trial participants from pharmacies not associated with the clinical trial sites?

Response: Yes.

7.13 Considerations/Requirements for the Use of Telemedicine

While not specifically addressed in the national legislation, telemedicine is permitted in Germany.

Ethics Committees tend to enquire about the privacy settings of any platform used for telemedicine purposes, as well as clarify if the software is considered a medical device.

It is important to consider which are the study-specific assessments that are under the responsibility of the investigator, (such as physical, neurological examinations, etc.) and if such assessments are related to the study endpoints. There may be instances where some assessments may be permitted to be conducted remotely (e.g. where a qualified nurse is physically with the study participant and the investigator is instructing or overseeing remotely via telemedicine). However, there may be occasions where those assessments can only be performed by a physician.

According to the response provided by BfArM on Q14 of the Appendix “National Provisions Overview” of the EMA's Recommendation paper on decentralized elements in clinical trials, see below:

BfArM's position shared on “Dialog Event” which took place in 2021 indicated that: “The measurement of vitals may be permitted where equipment has been provided to the participant, but physical examination of a participant may not occur remotely.”

Q14: Certain tasks/procedures carried out at home may require the supervision of the investigator (a physician). Is it allowed for the physician to supervise remotely?

Response: “In principle, yes, subject to the qualification requirements under national law for the medical personnel to whom a task is assigned; a number of medical tasks may according to national law only be performed by physicians (with a medical license to practice medicine).”

7.14 Considerations/Requirements for the Use of Wearables

Not specifically addressed in the existing national legislation, but support for their use may be found in the EMA's “Recommendation paper on decentralized elements in clinical trials” which makes some remarks with regards to wearables as part of handling data. 

References to Wearables as well as Bring Your Own Device (BYOD) can also be found within the EMA guidance on “Computerized Systems and electronic data in clinical trials”.

7.15 Considerations/Requirements for Remote Monitoring

According to the response provided by BfArM within the Appendix “National Provisions Overview” of the EMA's Recommendation paper on decentralized elements in clinical trials, remote monitoring may be permitted.

Q15: Is remote access to the medical records allowed by the monitor or auditor?

Response: Yes*. *In principle, yes, provided that the investigators can and do comply with their obligation to maintain the confidentiality of their patient's health records; therefore, the responsibility for answering this question is with the respective investigator. 

7.16 Considerations/Requirements for Digital Health Technologies (such as Platforms)

Not specifically addressed in the existing national legislation/guidance. However, considerations can be found within the EMA guidance on “Computerized Systems and electronic data in clinical trials”.