"Off-site monitoring", remote monitoring and centralized monitoring as an alternative to on-site monitoring of clinical trials in times of the COVID-19 pandemic and what we can learn from them for the future
First of all, I would like to briefly examine the various options for monitoring of clinical trials:
1. On-site monitoring
The CRA travels regularly to the trial site and compares the patient´s medical file with the entries in the eCRF on site, the CRA trains the site staff and checks the storage of the trial medication. Overall, the CRA will get a comprehensive picture on whether patient safety and data quality are guaranteed.
2. "Off-site monitoring"
In version 3 of the "Guidance on the Management of Clinical Trials during the COVID-19 (Corona-Pandemic) " from April 28 , 2020 , the EMA describes the "Off-site monitoring" in the form of telephone calls, video conferences, emails and other methods to check on the status of the trial or to perform training of study personnel.
3. Remote monitoring
Until now, remote monitoring was defined by the review of data which is available outside the trial site and is available electronically . Since most trial sites outside of the US do not provide the possibility to review EMRs only the review of the eCRFs remains, provided the trial site has entered the data. In addition, data in IRT, in electronic patient diaries, report of central laboratories etc. can be reviewed. However, a source data verification of the patient file cannot be carried out. The contact with the study staff takes place over the phone or potentially via video / web conference. Up to now it is not allowed in most EU member states to copy the patient file and to send redacted files to the CRA. The only authority that has considered this so far was the MHRA. This was revised with version 3 of the "Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic" from 28. April 2020. A distinction is now made between "Off-site monitoring" and remote monitoring. For the period of the pandemic remote monitoring of copied and redacted medical records or access to electronic patient records (if technically possible) is considered. Access to the patient file during a video / web conference is also counted as remote monitoring. Remote Monitoring should only be performed, if it is used in Clinical trials in the indication COVID-19 or in serious or life-threatening indications with no therapeutic alternative for datacleaning before database lock (Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic , Version 3, April 28, 2020). It is a requirement that this procedure is in line with national regulations (including temporary emergency regulations) and that data privacy rights of the study patients are maintained (Annex 1 of the Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) Pandemic , Version 3, April 28, 2020)
4. Centralized monitoring
Centralized monitoring is defined as review of electronic data, such as the eCRF, electronic reports of the central laboratory, electronic patient diaries etc.. Centralized monitoring usually complements on-site monitoring. At the time of the current pandemic with existing travel restrictions, centralized monitoring can also replace on-site monitoring for a limited time (in addition to other monitoring options which were already mentioned (“off-site” and remote monitoring).
The ICH GCP Guideline E6 (R2) and the FDA (Guidance for Industry Oversight of Clinical Investigations - A Risk-based approach to monitoring) recommends the combination of on-site monitoring and centralized monitoring (5.18.3 Addendum to the ICH GCP Guideline E6 (R2)) to increase the efficiency and success of monitoring. Centralized monitoring also supports the risk-based approach of monitoring.
Centralized monitoring was not implemented due to the current pandemic but was already introduced for many clinical trials previously.
The question remains what can we learn for the future and whether centralized monitoring would be able to replace on-site monitoring? Above all centralized monitoring in combination with " off-site monitoring " saves costs and time (remote monitoring, as described here, will certainly not prevail after the pandemic due to data protection reasons ).
On the one hand we are currently learning how important the implementation of digital processes is. On the other hand we can see that there are topics for which presence on site is needed e.g., it is more suitable for certain trainings of site staff to be carried out on site (e.g. trainings on IP processes). Certainly, on-site monitoring will persist but it will be reduced. It should be checked for each trial if Centralized Monitoring can be implemented to reduce on-site monitoring and to adhere to the risk-based approach. For the implementation of centralized monitoring sufficient case numbers (e.g. number of study patients) should be considered. Furthermore, a reduced number of monitoring visits will free up resources to instead being able to perform tasks, which can ensure high data quality and patient safety.
In addition, in case of another pandemic or emergency another advantage would be to being quickly abe to set-up a monitoring strategy without on-site monitoring for a limited period of time.
All sources were last opened on 21.05.20:
https://www.fda.gov/media/116754/download
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