On 20 March 2020, the European Medicines Agency (EMA) published Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic (the Guidance). The EMA jointly developed the Guidance with working groups from the European Commission and the national Heads of Medicines Agency (HMA).
The Guidance provides information on changes and protocol deviations that may be needed in the conduct of clinical trials during the COVID-19 pandemic. The Guidance includes a harmonized set of EU-level recommendations to ensure the safety of trial participants while preserving data integrity. The Guidance also advises how these changes should be notified to national authorities.
As clinical trials in the EU are authorized at the national level, this EU-level Guidance does not overrule guidance issued by national competent authorities, to the extent that there is any. Sponsors and investigators are advised to consult national guidance for relevant national notification procedures, as there is some divergence across EU Member States.
The EMA acknowledges that COVID-19 and the public health measures that have been implemented in response to the pandemic can result in challenges for the conduct of clinical trials. Quarantines, site closures, travel limitations, and supply chain interruptions, for example, may require alternative arrangements that lead to protocol modifications and deviations.
It is expected that sponsors and investigators base any decision to adjust the conduct of a trial on a documented risk assessment and implement measures that prioritize subject safety and data integrity. The EMA’s recommendations for potential changes include the following:
- The conversion of physical visits into contact by phone or telemedicine to ensure continuous medical care, identify adverse events and maintain oversight.
- Critical laboratory testing, imaging or other diagnostic tests to be conducted locally where subjects cannot reach the study site.
- The possible temporary halt of a trial, suspension of new participant enrollment, extension of a trial, or postponement of a trial or the activation of sites not yet initiated.
- A change in the distribution of the Investigational Medicinal Product (IMP) to ensure patients receive treatment and avoid unnecessary physical site visits. Generally delivery is expected to be from the investigator site to trial subjects, but direct sponsor to subject shipment may be possible in some Member States where national guidance permits. Sponsors must consider the practical implications of alternative shipping and storage arrangements for IMPs, including route of administration, stability during transit and storage conditions in a subject’s home. In the event of an urgent shortage of IMP, sponsors may also consider re-distribution between sites in accordance with GMP Annex 13.
- Where the Principal Investigator is indisposed for a period to delegate his/her duties temporarily e.g., to sub-investigator.
In relation to communication with authorities, the Guidance states that the relevant competent authorities and ethics committees must be informed in accordance with Directive 2002/20/EC and national laws where:
- a new event is likely to have a serious effect on the benefit-risk balance of the trial; such a change should be implemented as an urgent safety measure; or
- a change is likely to affect the safety or well-being of the participants and/or the scientific value of the trial but does not require immediate action; such a change should be submitted as a substantial amendment.
Notwithstanding the EMA’s Guidance, several Member States have issued national guidance on the management of clinical trials during the COVID-19 pandemic. In some instances, national notification requirements are not harmonized with the EU-level Guidance, leading to some divergence across EU Member States and the UK.
National competent authorities that have adopted guidance, include amongst others:
- The UK’s MHRA issued updated guidance on Managing clinical trials during Coronavirus (COVID-19) on 25 March 2020. The guidance expressly provides that if a trial has been halted due to issues related to COVID-19, there is normally no need to inform the MHRA; instead, the trial master file should include a note that the trial was halted, giving the reason why. Only if there is a direct participant safety issue should the MHRA be informed in the “normal way” (e., as an urgent safety measure). The MHRA also needs to be informed if a trial is halted due to a medicines supply issue. The guidance clarifies that a substantial amendment is not required for the use of phone calls instead of protocol-directed in-person study visits or where participant monitoring visits need to be reduced.
- Ireland’s HPRA issued Guidance on the Management of Clinical Trials during COVID-19 (Coronavirus) on 16 March 2020. The guidance has been updated to refer to the EMA Guidance and appears consistent with the EU-level position. The HPRA requires substantial amendments to be submitted to the Authority marked “COVID-19 relevant” and confirms that urgent safety measures can be used, where appropriate.
- Denmark’s DKMA issued updated guidance on Extraordinary measures for clinical trials due to COVID-19 on 16 March 2020. The guidance recommends that changes due to COVID-19 should be handled as urgent safety measures. The guidance also expressly allows a single notification to cover several clinical trials if it concerns non-protocol-specific changes. Once normal procedures are restored after the pandemic, notifications will need to be submitted individually .
- Norway’s NoMA updated its guidance on Management of Clinical Trials in relation to COVID-19 on 19 March 2020. The guidance states that NoMA defines all changes that must be made as a result of COVID-19 as urgent safety measures.
- France’s ANSM has issued guidance on COVID-19 – Ongoing clinical trials (available only in French). This states that if the enrollment of new patients is suspended, this should be notified to the ANSM and the ethics committee for information only, but if treatment itself is suspended, this should be notified to the ANSM and the ethics committee as an urgent safety measure and then followed up with a substantial amendment.
- The Netherland’s CCMO issued Advice for conducting clinical trials during the coronavirus restrictions (available only in Dutch) on 13 March 2020. This discusses certain changes that should be submitted as urgent safety measures and others that can be treated as protocol deviations and would not need to be reported. The guidance states that if a study is suspended, this must be notified to the ethics committee and competent authority immediately if this impacts patient safety or otherwise within 15 days.