Clinical trial monitoring

Clinical trial monitoring is a crucial element in conducting clinical trials, and is required under Federal law in the US. Monitoring aims to ensure patient safety and well-being as well as the reliability and accuracy of the data generated in the trial.[1]

Clinical research monitoring is typically performed by the trial sponsor, with the objective of affirming that participating investigative sites are adhering to the study protocol. A 2022 paper summarized various literature sources and guidelines on clinical monitoring, and synthesized the ideas into five key principles of clinical monitoring:[2]

1. Maintaining participant safety and being respectful of their rights
2. Ensuring reliable data
3. Ensuring the trial is being conducted according to applicable protocol(s)
4. Improving trial operations if required*
5. Preventing issues before they occur

The authors then surveyed 93 clinical trial monitors at a national meeting in the UK. With the exception of point #4, 96%+ of respondents agreed with each of the other principles listed above as being an important aspect of monitoring.

* 9% of respondents disagreed that improving trial operations was a primary purpose of trial monitoring.[2]

Clinical trial monitoring typically involves reviewing essential documentation, assessing data quality and completeness, overviewing adverse events and their reporting, and verifying protocol compliance, both at the site level and at the level of the sponsoring organization. In general, there are four prominent models of clinical trial monitoring:

• On-site or traditional monitoring
• Central monitoring
• Risk-based monitoring
• Remote monitoring

In this article, we focus on remote monitoring in clinical trials.

Remote monitoring in clinical trials

What is remote monitoring in clinical trials? It’s a cost-effective, time-saving monitoring model that doesn’t require trial monitors to visit each clinical trial site to review data. Instead, they assess data and other trial parameters virtually/remotely.

Before remote monitoring gained steam during the COVID-19 restrictions, clinical trial monitors would typically physically visit the trial sites every few weeks to manually inspect and review the data, facilities, paperwork, and staff performance/compliance, leaving notes if they had a concern or required specific answers.1 In remote monitoring, trial sponsors/CROs and their monitors use digital technologies to access and review data without having to visit the site.[3]

What is the difference between central monitoring and remote monitoring?

Remote monitoring and central monitoring or centralized monitoring refer to more or less the same concept, involving remote evaluations of sites and data from a single, distant (central/centralized) site. Under both of these monitoring methods, trial monitors don’t generally visit trial sites, except when and if queries arise that require further investigation via a physical site visit. This is precisely what makes them so attractive; travel time and costs are reserved for cases wherein it is fully warranted.

Remote monitoring vs. risk-based monitoring in clinical trials

Risk-based monitoring is a proactive, targeted, and strategic approach to trial monitoring. It makes use of increased connectivity and advanced data analytics to streamline and optimize error detection. Risk-based monitoring also aims to reduce the need for most site visits, again reserving visits for when they are necessary to resolve queries or issues. Risk-based monitoring, or RBM, involves five crucial components combined into one methodology/program:[4]

• Use of key risk indicators (KRIs)
• Centralized monitoring
• Remote monitoring
• Source data verification (SDV)
• Source data review (SDR)

Thus, in a simplified answer, we can say that risk-based monitoring is a form of remote monitoring that additionally applies a system risk identification and classification to further target and streamline monitoring tasks, focusing first and foremost on the highest-risk areas/operations.

Decentralized clinical trials and remote clinical trial monitoring

Remote clinical trial monitoring is closely linked to decentralized and hybrid trials, as such trials involve fewer trial sites and visits, or even none at all. As data is inputted remotely, monitoring can be performed from a centralized point by the sponsor, and the need for in-person site visits is removed. The reduced number of intermediate steps in data processing and lack of manual data transfer significantly reduce the risk of errors in the data.[3] Hybrid trials still involve some trial sites, and in-person site visits may be necessary for investigating any discrepancies that arise.

The adoption of decentralized and hybrid clinical trials accelerated greatly during COVID-19 lockdowns as new methods were needed to continue conducting clinical studies. As part of this shift, remote clinical trial monitoring also increased.[1] As clinical research monitors were often unable to travel to trial sites during the pandemic, sponsors considered new methods of sharing data, increasingly collaborated virtually, and explored remote monitoring solutions.[5] The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) also issued guidance on changes during the pandemic to facilitate continued trial progress while ensure patient protection and maintaining good clinical practice standards.[6]

Advantages of monitoring clinical trials remotely

Although remote monitoring comes with its own set of challenges and new workflows (more on this later), there are some undeniable benefits that remote monitoring of clinical trials offers, to sponsors, patients, and sites alike:

1. For sponsors: Real-time monitoring

Remote monitoring often translates into real-time monitoring; collected data is electronically transmitted almost immediately from source to EDC systems and other software systems in the sponsor’s workflow, allowing monitoring to begin essentially from the moment the data point is collected.[3] This offers many benefits, such as rapid identification of and response to adverse events, missing data, and potential issues with devices or software. Real-time monitoring also enables researchers to gain higher-precision insights into the efficacy of the investigational product, and to follow-up quickly with patients who miss an appointment or an expected data input time point.

2. For sponsors: Data quality

Remote monitoring of clinical trials by sponsors can also enhance data quality. With remote monitoring, a single document repository or database is usually used to track clinical trial documents, enabling clinical trial monitors to quickly identify errors or missing data and correct discrepancies, acting as a sort of on-the-fly data validation step and reducing the workload involved with data validation after data collection is complete. Features of inter-system integration and automation in data collection and processing workflows can be leveraged to further reduce the need for manual data verification. As data is continually verified for consistency and coherence between source, trial sites, and the central monitor, SDV and SDR are streamlined significantly.[5]

3. For sponsors: Regulatory compliance

Efficient, real-time remote monitoring from a central location enables comprehensive overview of data coming in from all sites and sources, which minimizes data gaps and leads to faster identification and correction of errors, key risks, and outliers, resulting in improved data quality.[3,4] Moreover, automated document routing ensures everyone receives consistent documents in a timely fashion.[4] All of these factors enhance regulatory compliance and support strong audit trails.

4. For sponsors: Reduced on-site monitoring

Remote clinical trial monitoring means reduced on-site monitoring; the trial monitor only has to visit trial sites in special cases when an issue needs to be addressed directly. This translates to less travel time and associated costs, as well as less redundancy in data verification, and thus a more streamlined use of resources and time.

5. For sites: Enhanced document management

When a clinical trial sponsor is monitoring the trial remotely, sites upload or input their data directly into a central server or a clinical data management system. This effectively reduces the use of paper documents and the related manual organization, storage, and data entry tasks, likely saving time (as long as workflows are implemented effectively) and reducing the use of physical resources and the generation of waste. It also supports a more collaborative data management and review process; sites can queue up documents for review by the monitor, who can flag potential issues for the site to address and fix quickly.[5]

6. For patients: Improved safety

Remote monitoring in clinical trials enables the trial monitor and the sponsor to identify potential adverse events much more quickly than in the case of on-site monitoring, where AEs may not be noticed until the monitor visits the site and reviews data collected on paper and in disparate documents and sources. A centralized data management system, on the other hand, can be set up to flag documents and actions that may require the monitor’s attention, such as protocol deviations and safety concerns. Customized alerts related to potential safety concerns can even be created, and thus aspects of patient safety and well-being are strengthened and enhanced.[3,5]

7. For patients: Engagement, wearables, and remote data collection

Remote data-entry technologies, such as wearable devices and electronic patient-reported outcomes (ePRO), tend to increase patient engagement as patients are not forced to travel frequently (or at all) to study sites and can play a more active role in their participation by inputting data themselves or interacting with wearable devices. Remote data collection can even be gamified or incentivized to further improve engagement and adherence to the study treatment protocol. Data collection can also be entirely passive (i.e., the wearable devices automatically collects data at specific intervals), further reducing any burden a patient may feel with self-reporting.

As long as they are properly calibrated and validated, remote data collection devices send raw and unbiased data directly to a remote database, also reducing potential sources of error such as recall bias.[3]

To summarize, remote monitoring ultimately leads to improved communication, enhanced data quality, and greater flexibility for all parties involved in a clinical trial.[4]

eClinical tools and tech solutions for remote monitoring

Technological solutions are an integral part of remote monitoring in clinical trials, facilitating the streamlined sharing, tracking, and management of data and documents. In December 2021, the FDA issued guidance on the use of digital tools for remote data collection in decentralized trials to promote the adoption of such trial models.[7] These guidelines emphasize that digital health technologies should be:

• Accurate
• Fit-for-purpose
• Usable
• Validated

Successful remote trial monitoring lies largely in the appropriate implementation of digital tools, which enable and support features such as secure data collection and sharing, automatic edit checks, document versioning, electronic signatures, controlled access and user permissions, automatic alerts, and which prevent unauthorized access and unnecessary manual document duplication and data transcription, all in a unified cloud-based server or repository.[4]

Workflows and tech stacks are highly customizable and may vary widely between sponsoring organizations. Technological tools used in remote trial monitoring are often integrated with one another, depending on the specifics of the protocol, and can include, but are not limited to:

Clinical trial management systems (CTMS) and clinical data management system (CDMS)

• eConsent
• Electronic trial master files (eTMF)
• Electronic quality management systems (eQMS)
• Electronic data collection (EDC) tools, including electronic clinical outcome assessments (eCOAs) produced during home healthcare visits and patient-reported outcomes (PROs)
• Telemedicine (study visits via phone or video call)
• Wearable devices like fitness trackers, digital therapeutics, and medical devices

Remote monitoring and the various technological systems it generally involves does introduce certain data security and regulatory concerns. Systems used for remote monitoring must be CFR Part 11 compliant. Sponsors and researchers must prioritize data privacy and security and ensure that patients sign waivers of HIPAA authorization for the sharing of protected health information electronically.[4] Moreover, clinical research staff must be thoroughly trained on the secure and correct use of such systems in order for them to be beneficial. Similarly, all devices involved, both at sites and those used by patients, must be properly validated to ensure that the data they produce or transfer is accurate and sufficiently controlled.

Challenges in the adoption of remote monitoring

Some of the tools listed above may be easier to implement and integrate into existing workflows than others. For example, wearable health technologies like smartwatches and fitness trackers have been largely accepted by the general public, and thus the barrier to the adoption of simpler devices by patients may be relatively low. On the other hand, more complex devices or those requiring constant re-calibration represent more challenges for sponsors and patients.

Likewise, the implementation of new tech systems and entirely new workflows at the organizational level may be met with some resistance. The initial adoption of new tech often requires an investment of time, effort, and money. Sew infrastructure (technological or otherwise) may be needed to maintain secure data management practices, and new workflows will require new SOPs and internal documentation and training. In general, the adoption of remote monitoring has faced obstacles with some sponsors and CROs being reluctant to pivot from their long-standing and familiar practices of on-site monitoring.

At the end of the day, the idea is that the time and effort invested in learning and integrating new tech solutions will eventually pay off through the multitude of potential benefits we discussed above.

The future of remote clinical trial monitoring

Despite the numerous and promising benefits that remote monitoring in clinical trials offers, it is not feasible for all studies, and it seems unlikely to become the singular solution for trial monitoring. In fact, the increased adoption of remote clinical trials and remote monitoring during the COVID pandemic hinted to the fact that there is still much value in on-site monitoring.[1]

Remote monitoring of clinical trials by industry sponsors appears to be most effective when it is supported by occasional on-site monitoring (in a hybrid model), rather than replacing it entirely. With the general oversight and rapid response covered by the remote monitoring program, supplemental on-site monitoring visits allow monitors to engage in strategic discussions and proactive problem-solving with investigators during site visits. It is yet to be seen whether further technological advances and increased adoption across the industry will further shift the balance toward remote monitoring methods, but as it currently stands, on-site monitoring brings particular benefits that can’t always be captured with purely remote monitoring.

Conclusion

Remote monitoring in clinical trials helps study sponsors assess and verify study data, optimize patient safety, and ensure protocol compliance, in real-time and from a centralized location, and with greatly reduced need for in-person site monitoring visits. When well-implemented, remote monitoring can streamline monitoring operations by taking advantage of the unified document repository and numerous automated processes (edit checks, versioning, etc.) that are supported by integrated technological systems. Nonetheless, remote monitoring is not appropriate for every trial model, and it represents a transition from long-standing monitoring methods – a transition which also involves new workflows, SOPs, staff training, and an initial investment for sponsors. It seems likely that on-site monitoring will remain prevalent for studies that aren’t fully decentralized, as site visits are still necessary for investigating and addressing certain issues, and since there are often some aspects of monitoring and quality control that simply aren’t feasible to perform remotely.

References

[1] https://www.pfizer.com/news/articles/is_remote_clinical_trial_monitoring_here_to_stay

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9526458/

[3] https://www.obviohealth.com/resources/remote-monitoring-in-clinical-trials

[4] https://www.ppd.com/blog/optimize-remote-monitoring-decentralized-clinical-trials/

[5] https://sites.veeva.com/resources/going-digital-with-remote-monitoring-key-considerations/

[6] https://ascpt.onlinelibrary.wiley.com/doi/full/10.1111/cts.12834

[7] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations