Overview
On April 27, 2020 The European Medicines Agency (EMA) released the Guidance on managing clinical trials during the coronavirus disease (COVID-19) pandemic, the European Commission added advice on distribution, data verification and communicating with authorities.
EMA Guidance Key Points:
Communication to authorities:
Initiating New Trials:
Priority is given to any new clinical trial application for the treatment or prevention of COVID-19 infection, and/or substantial
Ongoing clinical Trials:
All decisions to adjust clinical trial conduct should be based on a risk assessment by the sponsor (ICH GCP section 5.0). In case the risk assessment leads to actions that affect the trial as described in Table 1 the relevant NCA and/or Ethics Committees must be informed in accordance with Directive 2001/20/EC and national laws.
Sponsors are encouraged to take into account the limited capacity of regulatory authority assessors and Ethics Committees, and submit only high quality, complete applications containing only the necessary changes.
Mitigating Measures:
Urgent Safety Measures:
Urgent Safety Measures are required by the sponsor and investigator to protect the trial participants against immediate hazard.
- Information needs to be provided to the NCA and the Ethics Committee as soon as possible.
- The sponsor is expected to provide adequate information on the cause, measures taken and the plan for further actions.
Substantial Amendments:
A change is substantial when it has a potential impact on the safety or physical or mental integrity of the clinical trial participant, or on the scientific value of the trial.
- Submission of information is only obligatory if the amendment is a substantial amendment.
- If changes to the substantial amendments, do not require immediate action from the sponsor or investigator, these should be submitted as substantial amendment applications.
Other Measures:
“Other measures” are changes that are justifiable and related to COVID-19 but are not related to trial participants’ safety and do not have a serious effect on the benefit-risk balance for the trial participants and the scientific value of the trial.
- Must be notified as soon as possible taking into account national and local circumstances
- Sponsors are expected to submit to the relevant NCA and Ethics Committee the list of all changes with appropriate risk assessment and justification as well as follow-up actions when necessary.
- Cumulative changes must not have a negative impact on trial participants’ safety and/or on the integrity of the trial.
Table 1: Examples for the classification of different Mitigating Measures
Distribution of Investigation Medicinal Products (IMPs):
Changes in the distribution of the investigational medicinal products (IMP) may be necessary to prevent avoidable visits to sites and to provide the trial participants with needed treatments.
Changes in distribution of IMP may include the following:
- Measures that DO NOT create shortages of marketed medicinal products:
- Larger amounts of IMP than normally foreseen can be provided to the trial participant.
- It is recommended for all IMPs and non-IMPs in clinical trials that an appropriate stock is maintained to ensure treatment in case of distribution failure.
- Urgent Shortage:
- Urgent shortage of IMP at some sites or transfer of trial participants from one clinical trial site to another site.
- Re-distribution in accordance with GMP Annex 17 (section 47) should follow a written procedure established in cooperation with the Qualified Person or the person responsible for distribution of the IMP, and sites should be provided with enough information to ensure that the process can be performed securely.
- Delivery:
- The delivery should be done from trial sites (hospital pharmacies as applicable) to trial participants.
- Cost of Shipment:
- The sponsor should bear the cost of the shipment and should provide logistical assistance to the trial site if needed
- If a trial site is not able to handle the additional burden of IMP shipment to trial participants, the IMP may be shipped to the trial participants by a an independent distributor who is acting on behalf of the sponsor.
Remote source data verification (SDV):
Remote source data verification (SDV) will currently only be considered necessary for very few trials. It should focus on the quality control of critical data such as primary efficacy data and important safety data.
Remote SDV may only be considered during:
- The public health crisis for trials involving COVID-19 treatment or prevention o
- The final data cleaning steps before database lock in pivotal trials investigating serious or life-threatening conditions with no satisfactory treatment option.
In the case of these very few trials, principal investigators should make their own determination as to whether or not the situation at their clinical site allows any of the following options for remote SDV:
- Sharing pseudonymized copies of trial related source documents with the monitor; this may be done electronically where manageable by the site staff;
- Direct, suitably controlled remote access to trial participants’ electronic medical records;
- Video review of medical records with clinical site team support, without sending any copy to the monitor and without the monitor recording images during the review.
Regulatory Summary:
The Member States support the submission of large, multinational trial protocols for the investigation of new treatments for COVID-19. Sponsors are encouraged to submit such applications for assessment via an accelerated Voluntary Harmonization Procedure (VHP) when possible.
The developers of medicines or vaccines are invited to contact EMA as soon as possible using the e-mail address 2019-ncov@ema.europa.eu. EMA provides a full fee waiver and a fast-track procedure for scientific advice.
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