Skip to Content
Life Science Technology

Risk-Based Approach to Monitoring of Clinical Investigations – Halloran’s Review of FDA’s Guidance

In April of 2023, the U.S Food and Drug Administration (FDA) released “A Risk-Based Approach to Monitoring of Clinical Investigations, Questions and Answers, Guidance for Industry.”  This guidance is noted to expand on the prior guidance for industry, “Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring,” released in August 2013 and to clarify the recommendations contained within.

Here is our review around the guidance’s four key themes: questions concerning risk, developing your monitoring strategy, risk assessment as a continuous process, and the importance of a root cause analysis.

Questions Concerning Risk

The first series of questions concern risk, and more specifically, risk assessment, documentation of risk activity, and key risks to monitor. An important element that is highlighted is that the initial risk assessment should inform the development of the clinical trial protocol and associated investigational plans. As a best practice, cross-functional risk discussions should start prior to a finalized protocol; starting with either an approved protocol synopsis or a solid draft protocol.

Often, the protocol is developed first and then at a later timepoint, a risk discussion and assessment are carried out, but often not until service providers, such as a Clinical Research Organization (CRO), have been engaged and their Standard Operating Procedure (SOP) and risk assessment template are employed. This approach misses the opportunity to identify the Critical to Quality (CtQ) factors, specifically the parameters that are critical to ensuring the quality of the clinical trial. Early cross-functional discussions provide an opportunity to identify potential risks to critical processes, data, and the health of the clinical trial.

Developing Your Monitoring Strategy

Sponsor personnel are often stretched for time so there must be a balance between monitoring enough risks so that the rights, safety, and welfare of trial participants is maintained, but without monitoring too many risks so that the review becomes uninformative and a ‘check the box’ exercise.

The risks identified through the initial assessment are critical in defining the most appropriate monitoring strategy for the clinical investigation. Keep in mind, the risks identified do not need to be the same for all sites. Evaluation of investigative site experience and infrastructure are also two risk elements to consider.

With the use of Electronic Data Capture (EDC), sponsors are given the ability to assess the quality of the data on an ongoing basis and not just during an on-site monitoring visit. Taking all these parameters into consideration, a sponsor (in conjunction with a CRO, if utilized) should then develop a monitoring plan that defines the type and intensity of the monitoring activities. In working with sponsors, we often see that monitoring is still focused on 100% source document verification with the mindset that if you look at everything, you “catch” everything that is wrong. But this approach dilutes the focus of the most critical monitoring processes.

The guidance also addresses how centralized monitoring is beneficial in identifying anomalies across sites more quickly, and thus, allowing for quicker identification of potential issues for further investigation including the need for targeted focus on-site monitoring. 

Risk Assessment as a Continuous Process 

A risk assessment is not a one and done process. As noted in the guidance, a sponsor should monitor the important and likely risks and continue to monitor for additional risks as the clinical investigation proceeds and more risks are detected through review of monitoring findings, protocol deviations, and data review. Sponsors should not ignore the risks that are less likely to occur, but if they did occur, would have a significant impact on the clinical trial.

The Importance of a Root Cause Analysis

When items are identified during centralized monitoring, the key is to make sure these are evaluated. A thorough root cause analysis is required, and appropriate preventative and corrective actions need to be put into place. All this must be documented and communicated to the appropriate parties.

In our work with sponsors and their vendors, we often see a root cause analysis done too quickly and/or not thorough enough, resulting in the wrong cause being identified. Thus, any steps taken to correct the issue are essentially misaligned with the true reason the issue occurred in the first place and will most likely result in the issue reoccurring.

Sponsors and their vendors should seek out a resource that has experience and time to do a thorough assessment from the beginning. Furthermore, we cannot overemphasize that the documentation of all these activities is crucial. Missing this step and not having supporting documentation for a regulatory inspection is to be avoided. We emphasize this approach when working with sponsors to prepare them for inspections, and often, missing, or incomplete documentation is a common finding. 


In summary, the April 2023 guidance helps clarify some of the 2013 risk-based monitoring guideline information and adds more content and context around risk-based approaches in clinical trials.

Halloran Consulting Group helps clients navigate the continuously evolving risk-based approach to clinical trials by working with sponsors as part of their team, helping them develop their quality management system to incorporate all the required processes, as well as performing inspection readiness activities.

For additional questions about your risk-based monitoring approach, contact Halloran.