In the aftermath of the Covid-19 pandemic, there was a debate both on the limits of typical on-site monitoring visits and on whether alternative technology-based solutions should continue to be used, even under normal conditions.
As known during the pandemic, the monitoring activity at clinical sites has been strongly impacted and revolutionized. It is only partially preserved through remote and virtual monitoring solutions, replacing the traditional on-site visits.
However, the interesting and unexpected aspect of this experience is that a debate has opened both on the limits of the typical on-site monitoring visits and the opportunity to continue using alternative solutions based on technology.
During the Covid-19 pandemic, Exom Group, through its Virtual Site Monitoring (VSM) solution, has guaranteed trial continuity, data integrity, and accuracy, even though site monitors were not allowed to visit the testing centers. Considering the significant advantages not only economic but also operational compared to the traditional on-site visit, this new model could be considered among the options for monitoring the clinical trial in the future.
The limits of traditional on-site monitoring visits
There is no doubt that the traditional approach to monitoring and quality control of activities in clinical trial sites is expensive, intermittent, time-consuming, and often impossible, as occurred during the pandemic.
Also, crucial study data are not available and verifiable until the next monitoring visit, severely limiting the ability to manage sites, discover problems, and identify bottlenecks in real-time. Moreover, it is impossible to maintain constant and regular visibility of essential study documents and source documents.
The organization of on-site monitoring visits also represents a waste of energy as they have to be scheduled much earlier since they require the simultaneous presence of both the site staff and the site monitor and, in any case, disturb the daily routine of the clinical site.
On-site monitoring visit, how it works?
The main activities that the Monitor carries out regularly during an on-site monitoring visit can be summarized as follows:
- Review the Informed Consent Form (ICF) to ensure that each subject has been adequately informed and has given consent to the study prior to the completion of any procedure, by checking both the presence of patient’s signatures and the dates of any screening examinations against the date of the consent signature.
- Check for the presence of serious adverse events (SAE) and that they have been notified within the timeframe required by pharmacovigilance rules.
- Examine the protocol’s correct application to detect any deviations that may compromise data quality or patient safety.
- Compare the source documents with the eCRF data to detect any discrepancies between data.
- Carry out drug accountability and verify the conditions of storage, dispensation, and return of the experimental drug
- Check the completeness, correctness, and updating of the Investigative Site File (ISF) documents and assess their consistency with those present in the Trial Master File (TMF)
- Examine issues pending from previous visits
- Confirm the site’s appropriateness and check if there have been any changes in the clinical trial staff.
Towards remote monitoring
The move to remote monitoring could represent an important opportunity for changing the clinical trial operations even beyond the COVID-19 emergency period. Because it’s not just a mere reduction in Monitor’s travel time but also represents an exponential increase in contacts and visibility on the center activities, objectively documented and, therefore, ultimately generates better overall study quality.
We think of a routine on-site visit that still requires the sharing of many documents via email, leaving plenty of room for disorganization, follow-up, and even miscommunication, while the use of technology solutions designed specifically to support the Monitor’s remote activity increases the quality, integrity, and efficiency of the monitoring process.
During the pandemic, more or less effective technological solutions have been developed and used to perform virtually at least some
of the activities that the Monitor typically performs during the on-site visits. Unfortunately, these solutions are often limited to some functionality and are not integrated with the relevant clinical trial’s infrastructural and operational environment.
Virtual Site Monitoring: the complete and integrated solution by Exom Group
Virtual site monitoring (VSM) developed by Exom Group is based on applications integrated with the clinical trial’s digital ecosystem while ensuring the separation of management control and, therefore, compliance with the privacy requirements for clinical data protection (GDPR).
VSM offers a new and innovative way to support the investigator and Monitor’s relationship, leveraging a technology that preserves personal interaction while improving the monitoring process’s efficiency.
Electronic informed consent
Genius ENGAGE, an application for the electronic informed consent, eliminates the occurrence of any deviation in the consent process, guarantees the respect of all the steps in a controlled time sequence, and makes available the signed form in real-time. Issues related to the consent procedure that requires a lot of time for their resolution are virtually zeroed, reducing the commitment during the monitoring visit and avoiding any risk for the consent procedure’s validity.
Source documents verification (SDV)
The most challenging and time-consuming part during an on-site monitoring visit, is undoubtedly controlling the source data (SDV), compared to the data entered in the study’s eCRF.
Genius Site Vault is the Exom Group application that allows complete remote verification of original documents (rSDV). It is a digital workspace, totally independent of the study database and under the center’s staff’s sole and exclusive control. Only qualified and appropriately authorized center staff maintains full control over the certified electronic copies of the original documents uploaded to Genius Site Vault. And only the researcher can permit and disable access to these documents, limited to “viewing only” functionality for remote SDV, audits, ethics committee reviews, and regulatory inspections.
During the remote review of the original documents, the Monitor can check for any unnotified or delayed SAE, identify protocol violations or inconsistencies with the data entered in the eCRF, and then generate the relevant queries, which are automatically notified to the investigator through the Virtual Personal Assistant (Genius EVA).
In Genius Site Vault, source documents are organized by patient code and visit and are flagged with the status of the audit:
- with queries waiting to be answered
- with solved queries
- verified without problems
- no verification required
Through the Advanced Analytics & Machine Learning platform, Genius WIZARD, we generate metrics in real-time, on document upload date, review date, generated queries, response time, and the status and completeness of the rSDV per patient and visit.
The ability to view all historical revisions and generated actions helps to more quickly reconstruct the center’s monitoring history and thus facilitate the handover to a new site monitor.
At any time during or after the study, each center can generate an audit trail, in PDF format, of all uploaded documents, including metadata.
In terms of security, it should be noted that, in Genius Site Vault, all transactions are protected by an advanced and secure cryptographic protocol with audit trail to prevent unauthorized users from accessing or viewing the documents in Genius Site Vault. Records remain encrypted for unauthorized users.
The system is validated according to 21 CFR part 11 and compliant with the provisions of the GDPR. In this regard, it should be noted that there is no risk of privacy violation, as all patient’s clinical data always remain under the full and sole control of the experimental center.
Obviously, the use of Genius Site Vault must be previously agreed with the Principal Investigator (PI) and then clearly described in the study protocol and the informed consent form and approved by the local Ethics Committee. Given the technical and operational characteristics of the application described above, we do not believe it’s necessary to seek the approval of the hospital Data Protection Officer (DPO). However, the study Promoter will decide whether or not to get the DPO’s approval.
Control of Site File (ISF) documents
Another vital activity carried out during the monitoring visit is the verification of completeness, correctness, and updating of the documents in the investigative site file (ISF). Through the Genius eTMF /eISF application, the site monitor can remotely check the site file’s status at any time and verify its consistency with the Trial Master File.
Compared to the assessment made during the on-site monitoring visit, the remote site file control is continuous and not occasional. It also facilitates the investigator’s uploading of documents directly into the ISF, avoiding unnecessary delays and insecure shipments via regular mail.
Study drug accountability
A final qualifying aspect of the on-site monitoring visit is the study drug accountability. A purpose-built technological solution,Genius eDSM (Drug Supply Management), allows the remote tracking of the study drug, from the moment it leaves the warehouse, arrives at the hospital pharmacy that takes it in charge, and returns to the warehouse for final destruction. The application informs in advance the expiry date, removing the relevant kits from the possible assignment to patients.
Based on the number of returned drug units, it calculates, in real-time, the treatment compliance. Finally, also the physical inspection performed by the site monitor at the hospital pharmacy where the study drug is stored can be appropriately and effectively replaced with the recording of specific images and videos performed by the investigator. Such materials can also be attached to the visit report and archived in the eTMF, as objective documentation of the experimental drug’s storage conditions at the clinical site.
Regulatory implications for the remote Source Data Verification
Food and drug administration (FDA) and the European Medicines Agency (EMA) have been encouraging clinical trial promoters to explore more effective monitoring strategies, promoting a more risk-based approach, as indicated in the ICH GCP E6 R2 addendum of June 2017.
The recently published guidelines issued by both regulatory agencies for conducting clinical trials during COVID-19 restrictions support remote monitoring for centers’ supervision, including verification of source data. This procedure should be risk-based and should be limited to those data critical for monitoring while ensuring subject safety, data quality, and integrity.
Regardless of the method chosen for the remote SDV, the study promoter must first obtain written agreement from the investigator and, where appropriate, from the institution where the study is conducted.
In Europe, the General Data Protection Regulation (GDPR) provides some strict rules for collecting and processing data from subjects, including during the conduct of a clinical trial. The GDPR adds complexity to the remote verification of original data by requiring centers to anonymize documents before making them available on platforms that are not under their direct control. Therefore, it requires further on-site monitoring at a later date to confirm the attributability of the data to the trial subject.
Unlike many other similar solutions, the Genius Site Vault is fully controlled by the center staff who authorizes and disables access to site monitor for rSDV. As they would do during an on-site visit, so that, for all intents and purposes, the certified electronic copies of the original documents loaded into this workspace will never leave the logical perimeter and control of the hospital where they originated.
Can we think of creating permanent opportunities from what has happened? As it always happens, difficult situations lead to the identification of alternative solutions that not only allow us to overcome the current problem but even open up opportunities for efficiency and quality unthinkable with a traditional approach.
It is precisely the case with the monitoring of clinical trials where on-site visits are impossible. The technological solutions described above demonstrate how Virtual Site Monitoring can guarantee the complete control of the site’s activities, not in an occasional manner, as with on-site visits, but continuously for more timely and effective corrective actions.
Virtual Site Monitoring reduces monitoring costs by up to 50% and increases the objectively documented quality. However, since human contact is fundamental for a fruitful monitor-investigator relationship, we believe that some on-site visits should be maintained during the course of the study. Even if most of the activities can be effectively managed remotely, we will occasionally visit the center to confirm the correctness of the verified documents.
Although we are all confident and optimistic that the pandemic can be brought under control as soon as possible and that the aforementioned normal working conditions can be quickly restored, there is no doubt that some of the operational changes made necessary during the emergency situation should be considered for permanent use even in normal times.
We are aware that the current regulations and the GCPs do not allow the use of the remote SDV beyond the specific period of the pandemic. However, we are confident that objectively analyzing the risks and benefits of this new method and the experience gained during this period will contribute to removing the current bureaucratic limitations and prohibitions.
In the meantime, we appeal to the competent European authorities to rapidly amend the existing regulations to adapt clinical trial monitoring, even under normal conditions, to the technology’s new opportunities.