Clinical trials continue to evolve and so do the methodologies used to support and provide the vital clinical trial monitoring necessary to protect patient safety. The methods, techniques, and strategies used in our field change with the technology at hand, new regulations, and other challenges that may be present. In 2020, the biggest influence on the way our industry operates has been COVID-19. While the pandemic has limited the industry’s ability to access our investigative sites and perform onsite monitoring, the coronavirus has expedited the rise and use of – remote monitoring and centralized monitoring.
The 3 Types of Clinical Monitoring
The concept of monitoring patients/subjects is not new to a veteran researcher like yourself. However, as with many concepts, the types of clinical trial monitoring techniques can sometimes get muddled or potentially made more complex, and this confusion normally persists with the understanding of remote monitoring versus centralized monitoring.
In a recent webinar from DIA on COVID-19, Alyson Karesh from the Food and Drug Administration (FDA) outlined the types of clinical monitoring explained in a discussion guide from the FDA and Duke-Margolis workshop held in July 2019. Please note these are Alyson Karesh’s definitions and do not necessarily reflect the official position of the FDA.
Ms. Karesh’s role at the time of this Webinar July 28, 2020 with FDA was Director, Division of Clinical Trial Quality, Office of Medical Policy, Food & Drug Administration (FDA) and 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 by the monitor 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.
The Added Nuances of Risk-Based Monitoring
One cannot talk about remote and centralized monitoring without bringing up Risk-Based Monitoring (RBM). It is a critical component of the lexicon of modern monitoring topics. 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 is designed to identify “risks to human subject protections and data integrity,” and 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 monitor those activities
- Adjust monitoring methodology as needed
However, RBM is a very nuanced approach. Any monitoring technique needs to be tailored to the risks identified by the clinician, CRO, and/or Sponsor. While critical risks could be monitored any number of ways, including the types outlined above – On-site, Remote, and Centralized – the end effort is more often a combination of these methodologies. All three clinical trial monitoring methods can be used in concert for effective oversight, monitoring and for the 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 called “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. Specifically, this guidance covers how sponsors, CROs, and researchers can develop a monitoring approach. It involves the development of monitoring plans as well as how to communicate results.
The most recent guidance from the FDA regarding 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,” and it 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) but only for those trials that are related to COVID or tied to a pivotal trial that treats serious illnesses for which an unmet medical need exists within that indication or community.
Monitoring During COVID
The COVID pandemic limited the ability for 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 each speak to this reality. Remote access became critical for continuing clinical trials that were in progress and preserving subject safety throughout this difficult time. Central monitoring has helped analyze study data from afar while remote monitoring helped replace on-site visits when they were impossible. After COVID-19 is hopefully mitigated through forthcoming vaccines and treatments being developed, we fully expect remote monitoring and centralized monitoring to become an ever-present component of clinical trial conduct moving forward. As always, the way our industry conducts clinical trials is ever evolving in new and different ways.
More Articles in Our Clinical Trial Monitoring Series
Over the coming weeks, Pharm-Olam will take a deeper dive into the different clinical trial monitoring techniques and the technologies used to support them. As we release these updates, we will add links here to their location on our blog for ease of navigation and discovery. We hope you find these articles interesting and beneficial to your efforts in protecting data quality and patient safety in your clinical trials. Pharm-Olam, as a global award-winning CRO, is dedicated to creating a healthier world for all. Stay tuned for future updates in this series!