Understanding the 3 Types of Clinical Trial Monitoring
Clinical research continues to evolve. At the same time, the methodologies used to protect patient safety are changing. The techniques and strategies used in our field evolve with new technologies. New regulations and other challenges also have an impact.
In 2020, the biggest influence on the way our industry operates has been COVID-19. The pandemic has limited access to investigative sites and prohibited onsite monitoring. COVID has also spurred on the adoption of virtual monitoring.
The 3 Types of Clinical Trial Monitoring
The concept of monitoring subjects is not new to a veteran researcher like yourself. Yet, the types of clinical trial monitoring techniques can sometimes get muddled. This confusion starts with the understanding of remote monitoring versus centralized monitoring.
A recent webinar from DIA on COVID-19 centered on clinical trial monitoring. In one presentation, the Food and Drug Administration (FDA)’s Alyson Karesh outlined the different types of monitoring. Her role at the time of this webinar was Director, Division of Clinical Trial Quality.
Please note these are Ms. Karesh’s definitions as presented at that webinar and may not reflect the official position of the FDA.
Her definitions are as follows:
On-site monitoring involves in-person evaluation carried out by sponsor personnel or representatives at the investigation site.
Remote monitoring involves off-site evaluation performed away from the site at which the clinical investigation is being conducted.
Centralized monitoring involves analytical evaluation carried out by sponsor personnel or representatives at a central location other than the site at which the clinical investigation is being conducted.
Centralized vs On-site Monitoring
Centralized and on-site monitoring are frequently confused. It really comes down to the location of the clinical trial monitoring compared to the place where investigators analyzed the data collected. However, the two are not mutually-exclusive.
Centralized monitoring implies that there is a single location apart from the investigative site where study personnel analyze research data. The information these individuals examine could come from on-site monitoring or remote monitoring situations.
The Added Nuances of Risk-Based Monitoring
Risk-Based Monitoring (RBM) deserves a mention too. It is a critical component of the lexicon of modern clinical monitoring . Karesh defines RBM as “monitoring that focuses resources and oversight on:
- important and likely risks to investigation quality
- on risks that may be less likely to occur but that could have a significant impact on the overall quality of the investigation.”
By Karesh’s definition, risk-based monitoring identifies “risks to human subject protections and data integrity.” It is part of any “risk-based quality management system.”
Taking a risk-based approach to study quality and the monitoring of any clinical investigation has a simplistic focus:
- Identify potential threats
- Design a plan to track those activities
- Adjust monitoring method as needed
However, RBM is a very nuanced approach.
Any monitoring technique should reflect the risks identified by the clinician, CRO, or Sponsor. Critical risks could be monitored in any number of ways, including the types outlined above — On-site, Remote, and Centralized. However, the end effort is more often a combination of these methodologies. All three methods can be used in concert for effective oversight, protection of data integrity, and patient safety.
FDA Guidance on RBM
The FDA has issued three guidances on the use of risk-based monitoring in recent years.
The first is “Final Guidance: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring.” It was released in 2013. This guidance centers on sponsor oversight and study conduct. The end aim is to improve participant protections while improving data integrity.
In 2019, the FDA released “Draft Guidance: A Risk-Based Approach to Monitoring — Questions and Answers.” As the title suggests, this document expands on the previous recommendations the FDA outlined in its 2013 guidance on the subject. This guidance covers how sponsors, CROs, and researchers can develop a monitoring approach. It involves the development of monitoring plans as well as best practices for communicating results.
The most recent guidance from the FDA on risk-based monitoring came out in March 2020. It is called “FDA Guidance on Conduct of Clinical Trials of Medical Products During COVID-19 Public Health Emergency.” The document has gone through several updates since its initial release. This guidance helps sponsors and CROs navigate trial risks and patient safety during the COVID-19 pandemic.
EMA Guidance on Risk-Based Monitoring
In recent years, the European Medicines Agency (EMA) has also issued a series of guidances and papers on risk-based quality management.
In 2013, the agency released “Reflection paper on risk-based quality management in clinical trials.” In that document, the EMA refers to monitoring as a function of Good Clinical Practices (GCP). They describe quality controls as being a potential part of a centralized approach to ensure that submitted documents and clinical data checks are in order. This document is the equivalent of the FDA’s present position on Risk-Based Monitoring.
In April 2020, the EMA published “Guidance on the Management of Clinical Trials During the COVID-19 (Coronavirus) Pandemic.” The document explains that the EMA and the Heads of Medicines Agencies (HMA) will consider remote site data verification (SDV). However, this provision is only for those trials that are related to COVID or meets a significant need. For instance, a pivotal trial that treats an indication or community that has an unmet medical need could qualify.
Clinical Trial Monitoring During COVID
The COVID pandemic limited the ability of patients as well as Sponsors, CROs, and researchers to access sites. The EMA’s April 2020 document as well as the FDA’s 2020 guidance speak to this reality. Remote access became critical for continuing clinical trials that were in progress.
The approach also preserved subject safety throughout this difficult time. Central monitoring helped analyze study data from afar. At the same time, remote monitoring replaced many on-site visits.
The way our industry conducts clinical trials is ever-evolving in new and different ways. After COVID-19 is mitigated, we expect remote monitoring to become common in clinical trials.