Beyond Compliance: How ICH E6(R3) Is Redefining Clinical Trial Quality

The Food and Drug Administration (FDA) posted E6(R3) Good Clinical Practice (GCP) Guidance for Industry in September 2025. As in the previous E6(R2) document, E6(R3) has an overarching principle of upholding the rights, safety, and well-being of participants over the interests of science and society. However, the previous document was revised to address the increasing use of technology in clinical trials and to recommend a more proactive approach to risk management to improve trial conduct and data quality. A comparison between E6(R2) and E6(R3) is summarized into the three main points described below.

1) Embracing Digital Tools to Improve Access and Data Collection

In E6(R2), the FDA allowed the use of technology for performing centralized monitoring with secured and validated computerized systems. The FDA placed greater emphasis on data traceability, which was enabled by having an audit trail with time stamps. In E6(R3), the FDA still highlights participants’ electronic data safety as an important concern. Additionally, the FDA encourages investigators and sponsors to perform decentralized trials, which alleviate the burden of traveling to clinical trial sites for participants. The FDA now allows investigators to use electronic documents and formats, such as electronic informed consent forms and electronic signatures, in lieu of paper-based systems. Clinical data can also now be collected using validated wearables. 

All of these recommendations allow more flexibility that could result in an improved trial recruitment process, especially for trials involving pediatric participants or pregnant women for whom commuting is often a hurdle.

2) Moving From Risk-Based Monitoring to Critical-to-Quality Thinking

Next, in E6(R2), the FDA recommended a risk-based approach as a means to uphold clinical trial quality, which includes participant safety, data quality, and GCP compliance. The risk management cycle—also included in E6(R3)—comprises the following:

• critical process and data identification 

• risk identification

• risk evaluation

• risk control

• risk communication

• risk review

• risk reporting 

In a nutshell, risks in processes and data that are critical to human subject protection and reliability of results are identified and evaluated for their severity and likelihood. Then, sponsors can decide which risks should be reduced and which should be accepted. Deviations from quality tolerance limits then trigger evaluation for corrective action. 

In E6(R3), the risk management approach is slightly different. The cycle itself remains the same, but sponsors must now proactively identify critical-to-quality factors—those likely to have a meaningful impact on participants' rights, safety, and well-being and on the reliability of the results—and reduce risk proportionately.

3) Focusing Resources Where Quality Matters Most

The monitoring plan in E6(R2) was tailored to specific human subject protection and data integrity risks of the trial. E6(R2) also introduced a centralized monitoring and data review process to reduce the frequency of on-site monitoring. In E6(R3), the FDA still recommends both centralized and on-site monitoring. Additionally, the monitoring plan is tailored to identify potential safety risks, risks to data quality, and/or other risks to the reliability of trial results. The monitoring focuses on aspects critical to quality, and sponsors are required to perform ongoing verification of critical-to-quality data against source data.

So what do these changes mean for existing regulatory documents? 

As noted by Robin Whitsell, the president of Whitsell Innovations, Inc., E6(R3) is more likely to affect nonregulatory, ancillary documentation (e.g., monitoring plans and study manuals). To quote Whitsell, “Where regulatory documents are concerned, some clients have modified specific templates, but otherwise, we have not seen a big change associated with ICH E6(R3). The bigger shift will be the transition to the ICH M11 protocol template.”

Key Takeaways

• The new guidance document provides a more comprehensive approach to clinical trial conduct. 

• Risk management becomes more proactive and preventative rather than corrective. 

• The new document also clarifies the FDA's expectations regarding the use of technology in trials to aid data collection, safety monitoring, and participant recruitment. 

• Adoption of these recommendations is anticipated to result in more flexibility, safer trials, and improved overall data quality.

About the author: Grace Pohan is a freelance medical writer with an interest in regulatory writing. She earned her MASc in chemical engineering from the University of Waterloo and her BEng in bioengineering from the National University of Singapore. She obtained a certification in regulatory writing from the University of Chicago.