Summary of Key Considerations Outlined in the Third Edition of the EMA Guidance
The European Medicines Agency (EMA) has now published its third version of the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic. This guidance addresses the need for sponsors to change the execution of clinical trials during the global COVID-19 pandemic response.
The EMA recommends taking a risk-based approach for trials that remain active during the COVID-19 outbreak. While safety reporting requirements remain the same, the methods for capturing data will need to evolve.
Below is a summary of key points that EMA recommends considering for COVID-19 and non-COVID-19 trials at present:
The EMA suggests that sponsors and clinical trial sites need to agree on when starting new trials or determining how to continue or halt ongoing trials.
INITIATING NEW TRIALS
If you are looking to kick-off a new trial, ask yourself the following questions:
- Is my new trial feasible and necessary?
- What are the additional risks and mitigations required?
SITE ACCESS CHANGES TO ONGOING TRIALS
Access to sites will be limited or sometimes impossible due to the COVID-19 Response. The EMA recommends that Sponsors and sites consider the following measures:
- Converting physical visits into phone or video visits, postponing or cancelling visits to ensure that only strictly necessary visits are performed at sites
- Temporarily halting a trial at some or all trial sites
- Slowing or postponing recruitment of new trial participants
- Extending the length of the trial
- Delaying trials or activation of sites that have not yet been initiated
- Closing sites that cannot continue participation in any format
- Transferring participants to investigational sites away from risk zones, or closer to their home
- Moving critical laboratory tests to local labs, not site locations
CHANGES TO INFORMED CONSENT
The informed consent procedure for all clinical trials must remain compliant with the trial protocol as well as with European and national legal frameworks.
For trial involving COVID-19 patients, the following specific aspects should be considered:
- If written consent by the trial participant is not possible (for example, because of physical isolation due to COVID-19 infection), consent could be given orally by the trial participant in the presence of an impartial witness.
For all trials:
- There may be a need to re-consent already included trial participants; for example, if the risk-benefit profile has changed. However, sponsors should avoid the need for trial participants to visit investigator sites for the sole purpose of obtaining re-consent.
- If re-consents are necessary for the implementation of new urgent changes in trial conduct, alternative ways of obtaining such re-consents should be considered during the pandemic.
- 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 IN THE DISTRIBUTION OF IMPs
Changes in the distribution of the IMP may be necessary to remove avoidable visits to sites and to provide the patients with needed treatments. In these cases, sponsors should:
- Assess the risks relating to the product and consider any alternative shipping and storage arrangements.
- Develop alternative shipping and storage arrangements that does not compromise the treatment blinding.
CHANGES TO MONITORING
Sponsor oversight responsibilities, such as monitoring, and quality assurance activities need to be reviewed and modifications may be required. Risk-based approaches to monitoring should be taken to ensure the rights, safety and well-being of trial participants and the veracity of the data.
The EMA guidance suggest that adjustments to monitoring activities may include a combination of the following:
- On-site monitoring changes
- Use of centralized monitoring and central review of data collected
- Off-site monitoring activities
- Remote source data verification process in rare cases
The monitoring plan should then be updated with changes made in order to strike an acceptable balance between appropriate oversight and the capacity of the trial site. Despite these changes, robust follow-up measures must be developed and implemented when the COVID-19 situation is normalised.
The EMA acknowledges that the COVID-19 situation is likely to introduce more protocol deviations than normal. Measures to consider:
- Deviations should be reviewed regularly, and protocol amendments considered if warranted.
- GCP inspectors will take a proportionate approach to Deviations which occur during the pandemic,
- An increase in protocol deviations in relation to the COVID-19 will need to be assessed and reported in the clinical study report, following ICH E3.
- Prospective protocol waivers remain unacceptable and that patients should not be included in trials without proper eligibility assessment, including performance of planned tests, and written informed consent according to national laws and regulations.
SUMMARY OF KEY MESSAGES FROM THE GUIDANCE
- This guidance includes a harmonised set of recommendations, to ensure the utmost safety of trial participants across the European Union while preserving the quality of the data generated by the trials.
- All decisions to adjust clinical trial conduct should be based on a risk assessment by the sponsor and be appropriately documented.
- Risk based monitoring should be utilized during the pandemic and preparations to return to normal procedures after it is over need to be planned now.
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