Changes in trial-related activities

• Any changes in the clinical trial protocol due to the COVID19 pandemic, such as switch to remote treatment or discontinuation of trial-related activities (e.g., laboratory tests, medical consultation), require the submission of a substantial amendment and the approval by the competent authority as well as a favourable opinion by the ethics committee.

• However, sponsors may take immediate measures to protect the trial subjects from any imminent danger, but must also notify the respective authorities and ethics committee immediately.

• Trial subjects must be informed on any changed procedures with a supplement to the patient information and respective consent of the trial subjects has to be obtained.

  The EU guidance document suggests alternative procedures to obtain such consent, e.g., contacting the trial participants via phone or video-calls and obtaining oral consents supplemented with email confirmation. According to EMA, any consent obtained this way should be documented and confirmed by way of normal consent procedures at the earliest opportunity, when the trial subjects will be back at the regular sites. However, patient consent has to be provided in writing under German law (i.e. either by “wet-ink signature” or qualified electronic signature) before the adapted study procedures are implemented. The German guidance documents do not contain any clarification in this regard. We briefly discussed this aspect with BfArM and PEI: There are no legal grounds to deviate from the written form requirement beforehand. BfArM and PEI suggest discussing with the competent ethics committee, how to set up a procedure to ensure that trial subjects sign in wet-ink before any changes are implemented even during this pandemic (status of Monday, 30 March 2020).

Shipment of IMP to trial subjects

• It may be necessary that IMP is directly sent to trial subjects to ensure their safety and wellbeing or the evaluability of the trial data. Note that the guidance only applies to IMP, which trial subjects can use by themselves without the need for application by a doctor or nurse.

• Shipment via the trial site is preferred. Transport and delivery as well as receipt by the trial subject should be tracked.

• Only in exceptional cases, direct transport from the sponsor to the trial subject is allowed, where a “suitably qualified” service provider is engaged as trustee by the sponsor. The contractual arrangement between the sponsor and the service provider must provide for the pharmaceutical drug safety during transport as well as, at any time, the protection of the trial subjects’ personal data. Trial subjects should be provided with written instructions on storage and return of IMP.

• Shipment of IMP to trial subjects requires the medical supervision of the investigator. Where the trial site is not involved in the shipment, the investigator should confirm the dose and regimen prior to the shipment.

• The documentation requirements under ICH GCP for the receipt, consumption and return of IMP have to be ensured.

• Changes in the IMP supply have to be submitted to the competent authorities and ethics committee with any other protocol changes as substantial amendment (cf. above).

Site monitoring

• Where monitoring of clinical trial sites is currently required, remote monitoring by phone or video visits should be preferred. This includes the possibility to verify source data, e.g., via camera.

• Data privacy requirements must be complied with; especially trial subjects’ personal data must not leave the trial site.

• Monitoring may only be performed by sponsor’s authorized personnel as foreseen in the trial subjects’ consent documents.

• The specific activities must by be laid down in the list of processing activities as exception. Since the guidance only covers regulatory aspects, BfArM and PEI make the caveat that compliance with data protection requirements may be assessed by competent data protection authorities.

• All changes to the site monitoring must be included in the monitoring plan and/or manual, which together with all documentation on such monitoring activities must be included in the trial master file.

• Temporary changes to the monitoring do not require the submission of an amendment to the competent authority or ethics committee.

• The trial report must summarize the monitoring adaptions due the COVID19 pandemic.

• The sponsors must check periodically, whether the implemented changes have to be continued.

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