By the Association of Medical Ethics Committees in Germany and the Federal Institute for Drugs and Medical Devices (BfArM).

On 26.03.2020, the BfArM published "Supplementary recommendations to the European Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic" for clinical trials with pharmaceuticals on its homepage.

In the following recommendations for clinical trials with medical devices, these amendments have been adopted as far as transferable or adapted to clinical trials with medical devices.

All recommendations are aimed at this:

• to continue to ensure the safety and well-being of the trial subjects,
• to continue to ensure the suitability of the clinical trial to demonstrate the safety, performance or efficacy of the medical device, and
• to prevent an unnecessarily high burden on the investigator and the trial site.

Research with medical devices used for treatment or diagnosis of COVID-19 is of high social value. The knowledge gained from such research should therefore be made available to the Community in a timely manner. Data and samples should be made available to other research organisations where authorised to do so (e.g. by consent of the data subject).

1. Adjustments to the clinical trial in view of the COVID-19 pandemic

The sponsor of a clinical trial is responsible for the necessary adjustments to the clinical trial. If necessary, he shall, with the participation of the head of the clinical trial, the principal investigator, and the investigators, examine necessary and appropriate measures and then determine them in a binding manner.

These modifications to the clinical trial, such as

• recruitment (suspension, extension)
• of times, scope and implementation of follow-up
• the user of the investigational products (professional application for own use) require an amendment to the study plan.

The adapted clinical investigation plan must be submitted to the responsible federal higher authority (“Bundesoberbehörde”) and the competent ethics committee as an amendment via DIMDI.

All measures that imply a deviation from the original trial protocol must be justified and documented in detail until a corresponding approval is granted.

The trial participants must be informed about the changes and must declare their consent.

Furthermore, the sponsor must check all quality assurance measures such as monitoring and auditing and, if necessary, make new arrangements. All quality assurance modifications must be justified, documented and stored in the Trial Master File.

2. Amendment notifications of ongoing clinical trials due to COVID-19

All measures that involve a deviation from the trial protocol must be documented and justified in detail. Furthermore, they must be reported to the federal higher authority and the competent ethics committee(s) by means of a substantial amendment. The notification should make clear the link to the COVID-19 pandemic and the implications for the conduct of the trial (e.g., the recording and reporting of SAEs). For amendment notifications that affect safety reporting, the sponsor is requested to include a risk analysis of the impact of these changes on the safety of the clinical trial subjects and the validity of the data collected.

This recommendation also includes corrective measures taken by the sponsor and the persons carrying out the studies on their own responsibility in accordance with § 14a MPSV.

3. Recommendations for the implementation of remote monitoring

It must first be determined by a benefit-risk analysis for what purpose, at what times and to what extent monitoring remains necessary in the clinical trial in question despite the limitations imposed by the COVID 19 pandemic. Where this is the case, it is strongly recommended that remote monitoring in the form of telephone and/or video visits be limited to essential core data and processes.

This will typically include the data required for continuous benefit-risk assessment, such as verification

• compliance with inclusion and exclusion criteria
• the correct use of the test product and
• the complete recording of (serious) adverse events, and
• of the essential target parameters.

The possibility of remote access to source data may exceptionally be considered as a temporary solution during the COVID 19 pandemic. A possibility to provide such direct access would be camera access to prepared study documents and records. However, the essential requirements of data protection must be guaranteed. Documents or recordings containing personal data of trial subjects must not leave the trial site, not even as copies; thus, such data must not be permanently stored outside the trial site. Transmission of data and/or documents of any kind that goes beyond the mere transmission of a camera image content as well as the use of cloud solutions remain fundamentally inadmissible. The same applies to the transfer of such camera image content to third countries. The information and communication technology must be designed in such a way as to ensure transmission in compliance with the DSGVO (German name for General Data Protection Regulation). As a general rule, the established messenger services are not suitable for this purpose. In this context, please be referred to the "Whitepaper — Technical Data Protection Requirements for Messenger Services in the Hospital Sector" published by the Conference of Independent Data Protection Supervisors of the Federal and State Governments on November 7 2019.

It must also be ensured that monitoring by video camera is performed exclusively by the sponsor's authorized personnel (i.e. the clinical monitor) in accordance with the written consent of trial subjects.

The specific procedure must be included in the list of processing activities laid down in data protection legislation as a defined exceptional case with a start and end date.

Before implementing monitoring by video camera, it is necessary to extend and/or adapt the monitoring plan and/or the monitoring manual accordingly. The instructions provided in these documents should ensure a structured approach and adequate documentation. The amended monitoring plan and/or monitoring manual, as well as the documentation on the implementation of video monitoring or other adapted monitoring measures, should be stored in the Trial Master File. The necessity, suitability of and compliance with the specified changes shall be reviewed periodically.
The monitoring adaptations due to the COVID 19 pandemic shall be summarized in the trial report after completion of the clinical trial.

In Germany, the temporary adaptation of the monitoring plan and/or the monitoring manual does not require the submission of an amendment to the responsible higher federal authority and ethics committee according § 8 MPKPV (Ordinance on Clinical Investigations with Medical Devices, "Verordnung über klinische Prüfung von Medizinprodukten"), as these documents are usually not subject of the clinical trial authorisation and opinion, respectively.

4. Handling of the investigational medical device

Medical devices are so diverse that no general recommendation can be given here. Ultimately, the sponsor is responsible for the entire clinical trial and should decide, in consultation with the investigators, what action is necessary for each individual clinical trial during the pandemic.

1. For subjects who have already signed the informed consent form, it should be considered:

   1. whether the use of the investigational medical device should be deferred (until after the pandemic) If this is the case, the inclusion and exclusion criteria should be reexamined at a later date and the medical consultation provided to the subject should be repeated with a new signature and date on the informed consent form.
   2. whether, in the case of an urgent need for treatment, treatment is possible as part of clinical routine (outside the trial, e.g., with a CE-marked medical device).

2. If the procedure has already been completed, it should be checked whether follow-up examinations at the trial site are necessary for the safety of the person concerned or whether follow-up by telephone is possible.

5. Follow-up at home with investigational medical device, CE-marked medical device or without device (hereinafter referred to as medical device only)

Due to the impact of the COVID 19 pandemic, in individual clinical trials and/or for individual trial subjects, the dispatch of a medical device to the trial subject may be necessary either to ensure the safety and well-being of trial subjects and/or to maintain the continuation of the clinical trials in accordance with the protocol and thus the evaluability of the clinical trial data.

The shipment of medical devices to subjects is generally subject to the requirement that the necessary level of medical monitoring of the subjects is maintained in accordance with the protocol.

The following recommendations refer exclusively to medical devices that can be used by the subject or with the help of relatives or other persons already regularly involved in the subject's care.

If shipment of medical devices to subjects is necessary, shipment by the trial site itself is preferred under this pandemic exception. Shipment should be carried out in a manner that allows tracking of transport, delivery, and, if necessary, installation or other adjustments.

If a proper shipment by the trial site is not possible, for example due to capacity reasons, logistical reasons, or special transport conditions for the medical device, a direct transport commissioned by the sponsor may be accepted in justified exceptional cases, provided that the sponsor commissions a suitably qualified service provider. This service provider must be contractually obliged by the sponsor to undergo training, if necessary, and to maintain the pseudonymisation and, if necessary, blinding of the trial subjects vis-à-vis the sponsor by appropriate measures.

The conditions of transport, transfer, installation, and adaptation of the medical device must be part of the contractual arrangements, so that both the safety of the medical device and the protection of the privacy and personal data of the trial subjects are adequately addressed. Medical devices must be provided to the subject or a person authorized by the subject.

Prior to shipment of the medical device, the sponsor shall also provide written operating instructions in a language understandable to the trial subject.

6. Miscellaneous

The use of telemedicine must comply with the necessary standards, including data protection requirements.

If external service providers, e.g. study nurses, take over study-related tasks, it must be ensured that the source data collected by them are transmitted to the investigator and that the persons employed are subject to the instructions of the investigator and are required to report. The descriptions of the trial site must be adapted accordingly.

The trial subjects should be informed of the changed procedures (e.g., with a modified follow-up plan for home use) with a supplement to the subject information and should give their consent.