On March 1, 2018, FDA issued final guidance on E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1). This guidance updates the original ICH E6(R1) Good Clinical Practice (GCP) guidance to encourage implementation of improved and more efficient clinical trial procedures, such as electronic data recording and centralized monitoring, while continuing to ensure human subject protection and reliability of trial results.

The guidance provides a unified standard for the European Union, Japan, the United States, Canada, and Switzerland to facilitate the mutual acceptance of data from clinical trials. The guidance should be read in conjunction with other ICH guidances relevant to the conduct of clinical trials.

FDA’s updates to the original ICH E6(R1) GCP guidance primarily focus on quality management of trials and monitoring of trials.

For quality management, FDA recommends sponsors to implement systems to manage quality throughout all stages of the trial process. Quality management includes the design of efficient clinical trial protocols, tools, and procedures for data collection and processing, as well as the collection of information that is essential to decision making. FDA recommends that sponsors focus on trial activities essential to ensuring human subject protection and the reliability of trial results. Thus, FDA recommends that the quality management system use a risk-based approach regarding: (1) critical process and data identification; (2) risk identification; (3) risk evaluation; (4) risk control; (5) risk communication; (6) risk review; and (7) risk reporting. With particular respect to risk control, FDA recommends that the sponsor decide which risks to reduce and/or which risks to accept, using risk reduction approaches proportionate to the significance of the risks. FDA also recommends that sponsors establish predefined quality tolerance limits, and that upon detecting deviations from the predefined limits, sponsors evaluate whether action is needed.

Regarding trial monitoring, the guidance includes updated recommendations to assist sponsors in developing a systematic, prioritized, risk-based approach to monitoring clinical trials. The guidance provides that sponsors may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable and unreliable data. Review and statistical analysis of data from centralized monitoring can be used to: (1) identify issues with missing, inconsistent, or unexpected data; (2) examine data trends within and across sites; (3) evaluate for systematic or significant errors in data collection and reporting, or data integrity problems; (4) analyze site characteristics and performance metrics; and (5) select sites and/or processes for targeted on-site monitoring.