This article pretends to follow-up a previous publication we did covering the initial guidance that was provided by some of the European National Competent Authorities (NCA) with regards to the COVID-19 outbreak.

Since the situation keeps evolving, almost every day we have been notified by different media that another Competent Authority and/or Regulatory Body has released a new document with their recommendations on how to manage clinical trials during the COVID-19 pandemic. You can read some of these guidance documents by accessing the links below:

MHRA (UK)

• Published on 12Mar2020

• Published on 19Mar2020

AEMPS (Spain)

• Published on 16Mar2020

FDA (USA)

• Published on 18March2020

The European Medicines Agency (EMA), on the 20th March 2020, released a document that includes most of the current guidance across the European (EU) Member States, with the aim to serve as an EU-level harmonised set of recommendations “Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic”

The document clearly specifies that sponsors and investigators need to take into account that there might be specific national legislation and guidance in place, which they should consult and which can be used to complement the EMA guidance, or, with respect to particular matters may take priority over the EMA recommendations.

The guidance covers eleven main topics:

• Initiating new trials

• Changes in ongoing trials

• Risk assessment

• Communication with authorities

• Agreement with and communication to sites

• Changes to informed consent

• Changes in the distribution of the IMP

• Changes to monitoring

• Protocol deviations

• Reimbursement of exceptional expenses

• Initiation of new trials aiming to test new treatments for COVID-19

Risk Assessment  

[ICH GCP E6(R2) section 5.0 Quality Management]

The sponsors need to perform a risk assessment for each of their ongoing trials (and the related investigators) prioritizing for the clinical trial most critical tasks and the best way to maintain them.

The ability to confirm eligibility and to conduct key safety assessments and trial evaluation is of particular importance

The measures implemented should be focused on subject safety and data validity, prevailing the subject health and safety in case of conflict.

All the relevant parties must participate in the risk assessment exercise which should be reassessed as the situation evolves. The initial risk assessment and the subsequent re-assessments should be properly documented.

All the decisions implemented by the sponsor to adapt the clinical trial conduct should be based on a risk assessment

Changes to Informed Consent

Even re-consent of already included trial participants would be necessary, it should be avoided that subjects visit investigator sites for the sole purpose of obtaining re-consent.

If re-consents are necessary, because urgent changes in trial conduct must be implemented (mainly expected for reasons related to COVID-19), alternative ways of obtaining re-consents should be taken during the pandemic. For example:

• Contact the trial participants via phone or video-calls and obtaining oral consents supplemented with email confirmation.

• Any consent obtained this way should be documented and confirmed by way of normal consent procedures at the earliest opportunity when the trial participants will be back at the regular sites.

Changes to Monitoring and Quality Assurance Activities

The majority of the sponsor oversight activities, such as on-site monitoring and audits, need to be adapted due to the current travel and site restrictions and /or availability.

Temporary alternative approaches considered are implementing phone or video visits. The EMA pointed the following considerations:

• The burden of the introduction of any alternative measures for the sites (in terms of time and staffing during the COVID-19 pandemic) should be considered in order to strike an acceptable balance between appropriate oversight and the capacity of and possibilities at the site.

• The alternative approaches should only be performed in agreement with the investigator sites.

• The limitations and risks of such methods and the requirements for data protection should be taken into account.

• The alternative arrangements need to be adequately documented.

• Robust follow-up measures must be planned and be ready to be implemented when the situation is normalised.

Remote source data verification as part of remote monitoring or remote audits. For example, providing the sponsor with copies of subjects’ medical records or remote access to electronic medical records) is currently not allowed in most of the EU member states as it might infringe subjects’ rights.

The provision of redacted/de-identified pdf files will not be acceptable either, as it puts extra burden on the site staff.

Some NCAs have started considering temporary solutions related to remote access providing that methods can be used restricting the access to the trial subjects’ records. This option should however be clarified with other relevant authorities such as, for example, the Ethics Committees and the data protection agencies. This approach will not be allowed unless a member state has given specific guidance allowing it.

Protocol Deviations

Since the COVID-19 situation is expected to introduce more protocol deviations than normal, the EMA expects that the sponsor escalates and manages such protocol deviations in accordance with their standard procedures.

A proportionate approach will be taken by the GCP inspectors when deviations are reviewed during inspections, in particular where the best interest of the participant is maintained, and the participant is not put at risk

An increase in protocol deviations in relation to the COVID-19 situation will in itself not trigger the actions required by GCP [ICH GCP E6 (R2) 5.20 Noncompliance]. However, all these deviations need to be assessed and reported in the clinical study report (CSR), following ICH E3 Structure and Content of Clinical Study Reports.

Conclusion

Even if the EMA has provided more clear guidance to handle clinical trials under the current situation, the main responsibilities on how to proceed and what mitigation actions to implement still sit with the sponsors.

Talking about risks, I see quite a lot of risks here.

Let’s see if the inspectors take a proportionate approach when reviewing deviations or assessing the alternative plans implemented by the sponsors without close supervision and/or approval by the regulators once we return to normality.

I hope it is not too late.

We cannot forget principle 2.3 of ICH GCP “The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society”.