ICH E6(R3) Annex 2 Draft Version is Now Available!

12/23/2024

Photo by NCI on Unsplash

On November 6th, 2024, the International Council of Harmonization (ICH) published the draft version of ICH E6(R3) Annex 2, a long awaited update to the good clinical practice (GCP) section of the ICH Harmonized Guidelines. The U.S. Food and Drug Administration (FDA) released the original ICH E6(R3) draft version in June of 2023 following the release of the Final Concept Paper for Annex 2 in May 2023.  Annex 2 is intended to address technological and methodical changes in trial planning, design, and conduct that have developed since the release E6(R2) in 2016. Annex 2 presents a new structure of the guidelines that is easier to read and updates to the content in an effort to keep the guidelines relevant in the ever-changing clinical trials ecosystem.

Annex 2 encourages the implementation of new trial design innovations that have gain popularity in recent years. These innovations have been the focus of recent FDA draft and final guidance for industry as well as many of our previous blog entries (Links to recent entries are at the bottom):

  • Decentralized elements: these are defined as trial-related activities that are conducted outside the investigator’s location or study site including trial visits from the homes of trial participants or remote visits conducted exclusively through digital health technologies (DHT). While the concept of decentralized elements in clinical trials has been in the works for many years, it gained traction following the COVID-19 pandemic that prevented most trial visits from taking place in person. The FDA’s current stance on decentralized elements is outlined in their final guidance “Conducting Clinical Trials With Decentralized Elements”.   

  • Pragmatic elements: Annex 2 defines it as integrating aspects of clinical practice into the design and conduct of a clinical trial, these are elements that are intended to streamline data collection, trial design, and endpoints. This includes broader eligibility criteria, ease of recruitment, and simplified protocols. Supplementary information as well as FDA’s progress with pragmatic elements can be found on their website under “Project Pragmatica”.

  • Real-world data (RWD): RWD in clinical trials is the use of any data that contains a patient’s health status from any source outside of the trial that may be used to ascertain endpoints/controls or serve as an external control. RWD includes, but is not limited to, be electronic health records, registries, and claims. The FDA’s most up to date opinions on RWD in clinical trials is summarized in their final guidance “Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products”.

Updates in Annex 2 place more responsibility primarily on Investigators and Sponsors but also Institutional Review Boards (IRB) when it comes to trial conduct, ethics, and the protection of trial participant’s rights, safety and well-being. IRBs are encouraged to pay close attention to the privacy and confidentiality of trial participants data especially in trials that incorporate the innovation mentioned above. Responsibilities of the Investigator in Annex 2 include communication with IRBs/IECs and novel informed consent considerations, especially when choosing the media on which to present the information. Over half of the Annex is dedicated to the changes in the Sponsor’s responsibility which includes protocol and trial design, consent/permission considerations for RWD, remote data collection considerations, and privacy and confidentiality considerations.       

The terminology used in Annex 2 has also changed and new definitions have been added to the glossary. Terminology changes include:

  • Using “trial participants” instead of “subjects” when referring to individuals who are participating in a trial

  • Using “source records” in place of “source documents and data” when referring to any original document or certified copy on any media (ex. paper, PDF, video etc.)

Added terms and changed definitions in to the E6(R3) include:

  • Assent: Affirmative agreement of a minor to participate in clinical trial. The absence of expression of agreement or disagreement should be not be interpreted as assent.

  • Audit Trail:

    • R2: Documentation that allows reconstruction of the course of events.

    • R3: Metadata records that allow reconstruction of the course of events by capturing details on actions (manual or automated) performed relating to information and data collection and, where applicable, to activities in computerised systems. The audit trail should show activities, initial entry, and changes to data fields or records, by whom, when and, where applicable, why. In computerised systems, the audit trail should be secure, computer generated and timestamped.

  • Suspected Unexpected Serious Adverse Reaction (SUSAR): an adverse reaction that meets three criteria: suspected, unexpected and serious. (Definitions for the three criteria are also in the glossary).

The entire draft guideline as well as supplementary information can be found on the ICH website. This is a significant milestone that will have many repercussions throughout the field of clinical research, and at Clinical Pathways we will be keeping you up to date on all relevant future developments through our blogs and newsletters. To ensure our clients are well informed of the changes to the ICH GCP, our training courses are being renovated with the latest guidance from ICH E6(R3). E6(R3) still remains part of ICH E8(R1) which is the umbrella guideline that serves as a map of all the ICH “E” family sections. Clinical Pathways offers an interactive eLearning course on this foundational guideline which can be found here. For a full list of available services and to sign up for our blog and newsletter, please visit our website at; https://www.clinicalpathwaysresearch.com/.  

-The Clinical Pathways Team

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