Introduction
EMA guidance
FAQs


Introduction

COVID-19 is having a significant impact on clinical trials due to its affects on EU healthcare systems, including:

  • limited or no patient contact;
  • restricted access to trial sites;
  • investigational medicinal product (IMP) shortages;
  • trial protocol changes; and
  • quarantined healthcare professionals.

The pandemic is not only compromising effective patient treatment, it will also significantly affect ongoing and planned clinical trials, which are crucial for developing medicines and vaccines. Sponsors and investigators must therefore adapt their mangement of clinical trials, and this article addresses what should they be aware of.

EMA guidance

On 20 March 2020 (last amended on 28 April 2020) the European Medicines Agency (EMA), the European Commission and the Heads of Medicines Agencies (HMA) published the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic. In brief, according to the guidance, the effects of COVID-19 on ongoing studies, on adding a new site to an existing trial, on ongoing recruitment and inclusion of new trial participants or on the start of a new trial should be considered.(1)

As the changing circumstances surrounding the COVID-19 pandemic are likely to lead to rapid changes to guidance on clinical trials, sponsors and investigators should monitor relevant documents for revisions.

Although the EMA emphasises that research and development relating to therapeutics for treating or preventing COVID-19 infection is critically important and that such clinical trial applications must receive preferential treatment, clinical trial regulations must nevertheless be observed. This article outlines how clinical trials should be conducted in the face of COVID-19-related obstacles.

FAQs

How should risk assessments be conducted?
In light of the increased risks associated with COVID-19, trial participants' health and safety are particularly important and must be carefully weighed against the anticipated benefits for the participant and data validity. Thus, sponsors must carry out a risk assessment for each ongoing trial and investigators must carry out a risk assessment for each participant.

In case of conflict, trial participants' safety prevails. Any risk assessment must be kept up to date depending on changes in the given circumstances.

Is it possible to initiate new trials?
In general, yes. However, sponsors should critical assess whether to start new clinical trials or to include new trial participants in ongoing trials. Additional risks to trial participants should be addressed in the risk benefit section of the trial protocol, as well as risk mitigation measures. In any case, trial participant safety is paramount, especially when additional challenges arise due to COVID-19.

Further, according to the EMA guidance and national supplementary documents, priority should be given to clinical trials for COVID-19 treatments and diseases relating thereto, as well as trials for serious diseases with no satisfactory alternative treatments.

How should clinical trials for COVID-19 treatments be initiated?
Submissions of large-scale, multinational trial protocols for the investigation of new COVID-19 treatments are explicitly welcome. The EMA provides a full-fee waiver and a fast-track procedure for scientific advice (for details and guidance documents see here) and implemented initiatives for the acceleration of development support and evaluation procedures for COVID-19 treatments and vaccines, such as the COVID-19 EMA pandemic Task Force (COVID-ETF) and a specific compassionate use process (for details see the guidance document available here). Developers of medicines or vaccines are invited to contact the EMA as soon as possible by emailing [email protected].

How should ongoing trials be conducted?
With respect to ongoing trials, sponsors must conduct a risk assessment of whether and to what extent measures such as temporary interruptions to a trial or based on individual sites are necessary, or whether postponing or extending the trial may be recommended. Further, sponsors should consider modifying a trial if required for any health issues associated with trial participants. According to the guidelines, such modifications may include:

  • transferring trial participants to other trials;
  • suspending or slowing recruitment of new trial participants;
  • postponing or stopping visits to ensure that only essential visits are made to inspection sites;
  • establishing or replacing on-site visits with teleconference meetings;
  • closing trial sites;
  • including study sites that have not yet been part of the trial; or
  • other measures to ensure patient safety.

Can recruitment processes continue?
Clinical trial sponsors must evaluate whether continued recruitment during the COVID-19 pandemic is appropriate or should be suspended.

If recruitment is to be suspended, an amendment notification must be submitted to the competent higher authority, but relaxations of the formal procedure are possible (eg, for simplification purposes, email notifications may suffice instead of official forms). To resume recruitment, a change notification (subject to approval) must be submitted to the competent higher authority and the responsible ethics committee.

How should deviations in clinical trial protocol be managed?
COVID-19 is causing considerable delays in clinical trials, which in turn result in protocol deviations. Therefore, sponsors should evaluate the pandemic's impact on the trial designs of ongoing or planned clinical trials.

The EMA has acknowledged that the COVID-19 situation is likely to result in more protocol deviations than normal and expects sponsors to escalate and manage such deviations in accordance with its standard procedures. Good clinical practice (GCP) inspectors should act reasonably when reviewing such deviations, particularly if clinical trial participants are under no risk and their best interests are maintained.

Contacting the competent authority (eg, the EMA) at an early stage may help when (for example) change notifications are required as part of clinical trial protocol.

Have safety reporting requirements been relaxed?
Safety reporting requirements for clinical trials continue to apply during the COVID-19 pandemic. This includes both investigators' obligation to immediately report serious adverse events (SAE) to sponsors (unless otherwise specified by trial protocol) and sponsors' reporting obligations towards authorities and ethics committees.

If, in connection with SAE reporting, a trial participant is unable to visit the site in person, initial communication with the investigator may take place by phone to decide whether the participant's appearance in person (eg, for further testing) is necessary based on safety considerations.

Will audits still be conducted?
The EMA guidance outlines that, in the current situation, audits should generally be avoided or postponed. Still, if permitted and happening, audits must be conducted according to applicable local and/or social distancing restrictions. Exceptions may be justified (eg, critical trials or audits to investigate serious non-compliance).

How should trial participants' informed consent be obtained?
If obtaining written informed consent from a trial participant is not possible (eg, due to physical isolation), consent may be given orally in the presence of an impartial witness. Further, the trial participant and the person obtaining consent may sign and date separate informed consent forms.

Potential COVID-19 trial participants could lack the ability to consent due to the severity of their medical condition. In this case or when minors are included, consent must be obtained from a legal representative. In case of acute life-threatening conditions where it is impossible to obtain prior informed consent within the therapeutic window, informed consent must be acquired later (if permitted under national legislation).

The need to reobtain a trial participant's consent during an ongoing clinical trial does not justify an on-site visit. Instead, consent may be obtained by phone or video conference followed by email confirmation. However, an updated information consent form must be sent to the trial participant in advance and everything must be documented properly.

How should clinical trials be conducted under increased protection measures for trial participants?
During the COVID-19 pandemic, as under normal circumstances, clinical trials must ensure that participants receive a high level of protection. To this end, the following measures are advised.

Remote monitoring
Sponsors' monitoring and quality-assurance responsibilities must be reassessed. On-site monitoring should consider national and local restrictions and the urgency and availability of site staff. Alternatives should be considered.

Remote access to source data may sometimes be a temporary solution during the pandemic. While trial documents and recordings may be reviewed by camera and video transfer, essential data protection requirements must be met. Documents or recordings containing trial participants' personal data must not leave a trial site. As such, commonly used messenger services are not deemed suitable for this purpose.

Phone and video visits must be carried out with trial participants' consent. Before implementing video monitoring, it is necessary to extend or adapt the monitoring plan or manual accordingly. The amended monitoring plan or manual and the documentation on the implementation of adapted monitoring measures should be stored in the trial master file.(2)

Shipping IMPs to trial participants
In order to avoid on-site visits by trial participants, it may be necessary to send IMPs directly to individuals. With such approach, the required level of medical monitoring must be maintained in accordance with the trial protocol. Sufficient attention must be paid to the safety of the medicinal product and the protection of the trial participant's privacy and personal data.

Strict documentation of transport, delivery, consumption and return is crucial. Written instructions for storage and return of IMPs must be provided to the trial participant. If the investigator is unable to send IMPs, a transport service commissioned by the sponsor and carried out by a suitably qualified service provider may be accepted in exceptional cases. Still, this is to be conducted on an anonymous basis (ie, trial participants must remain unknown to the sponsor). IMPs must be delivered directly to the trial participant or an authorised representative and must not be left with a neighbour or deposited at a storage location.

If a change in the protocol is necessary in this context (eg, due to remote treatment or the omission of laboratory tests or medical consultations), the approval of the responsible higher federal authority and a consenting evaluation by the ethics committee is required. The trial participants must also be informed and must give their consent.

For further information on this topic please contact Magdalena Kotyrba or Tobias Maier at Eversheds Sutherland (Germany) LLP by telephone (+49 89 54565 0) or email ([email protected] or [email protected]). The Eversheds Sutherland (Germany) LLP website can be accessed at www.eversheds-sutherland.com.

Endnotes

(1) Although this guidance aims to serve as an EU-level harmonised set of recommendations, national legislation and guidance may already be in place. For example, further to the EMA guidance, in Germany the higher federal authorities, the Federal Institute for Medicines and Medical Devices and the Paul-Ehrlich-Institute issued supplemental national guidance on 26 March 2020 on required changes to clinical trial protocols, the supply of investigational medicinal products and the conduct of site monitoring during the COVID-19 pandemic.

(2) For example, in Germany the temporary adaptation of the monitoring plan or manual does not require the submission of an amendment to the responsible higher federal authority and ethics committee (Ordinance on the implementation of GCP in the conduct of clinical trials on medicinal products for use in humans (GCP Verordnung)).