ICH E6(R3) Revisions:  Is Your Team Ready for the Coming Changes?  

With potential changes in the design and development process on the horizon, we discuss the upcoming ICH E6(R3) revisions and the impact on clinical research 

A Look Back at Revision Two 


In 2016, ICH E6(R2) was introduced, focusing on trial participant protections and data integrity. The aim was to achieve these goals via better study design, conduct, and oversight, with sponsors and CROs taking on most of the additional responsibilities. Identifying and tracking risk-prone areas before a trial started during the protocol development process allowed sponsors and CROs to proactively establish critical tolerance levels, mitigation plans, and document the acceptance of certain risks around these risk-prone areas.  

ICH E6(R2) made it clear that sponsors were responsible for implementing a quality management system that focused on participant safety and the reliability of results. It also outlined a “risk-based” approach which moved the industry toward proactive quality as opposed to managing quality through retrospective quality checks (e.g., 100% SDV and other QC-style checks). Accordingly, the industry saw an increase in risk-based and statistical monitoring tools, although many sponsors and CROs still struggled to implement effective solutions. However, it seems clear that the increasing use of these tools and procedures will eventually allow more immediate identification of potential safety, compliance, and data integrity issues.   

While most experts agree that R2 was a move in the right direction, much of its guidance and further adoption was still left to individual interpretation. Clinical trials continue to see an increase in complexity and innovative digital health technologies. This trend has left many sponsors, CROs, and research sites confused about how they can implement the new guidance to increase effective trial management and produce reliable results and inspection-ready programs.   


How R3 Is Expected to Clear the Air 


ICH E6(R3) is expected to give more comprehensive and refined guidance to many areas of clinical research, including specific considerations for interventional compared to non-interventional trials. Although many of the ten original ICH E6(R2) principles have not changed, ICH E6(R3) will reorder and further elaborate on many of them. The ICH E6(R3) draft will also introduce a few new principles not found in ICH E6(R2).  

1. Quality should be built into the scientific and operational design and conduct of clinical trials 

Quality should be proactively included in the design and conduct of clinical trials, starting with design of the protocol and study procedures. This ‘quality by design’ approach involves using a planned, multidisciplinary method to promote the quality of the protocol and study materials, and defining clear processes to achieve quality throughout the study conduct. Areas that are critical to the success of the study objectives should be identified early and included in the quality process, with focus on protection of participants, and ensuring the reliability and interpretability of the trial results so that sound decisions can be made based on the trial results. 

2. Clinical trial processes, measures, and approaches should be proportionate to the risks to participants and to the reliability of trial results.  

Trial processes should consider the risks inherent in the trial and the importance of the data being collected. To do this, the sponsor must first take time to understand the risks inherent in the trial and explore options to manage these risks. Risks outside of standard medical care should be a focus, and sponsors can consider whether treatments and procedures in the trial are being administered in the same context as in clinical practice in order to assess comparative risk.  Risks which have an impact on the quality factors deemed critical to the trial should be accounted for in the prospective quality design process. 

3. Roles, tasks, and responsibilities in clinical trials should be clear and documented appropriately 

The sponsor and investigator may still delegate trial-related responsibilities (for example, to contractors and vendors), but they are ultimately responsible for the quality and integrity of the trial data and safety of participants. Agreements should clearly define the roles, tasks and responsibilities to be delegated, and the sponsor must plan and describe how oversight will be ensured. Choosing a CRO with a demonstrated record of quality, and a sponsor qualification audit of the CRO can help a sponsor choose a CRO to partner with that has the same culture of quality to execute delegated tasks. 


Preparing for Implementation and Adoption of ICH E6(R3) 


Many sponsors and CROs were aware of this new direction based on ICH E6(R2) and may already have robust systems in place. In addition, COVID-19 accelerated the adoption of many of the new technologies and the implementation of new processes required to be compliant. However, sponsors and CROs should be aware of the potential impact on operations and outsourcing processes. Some considerations include:  

  • Thinking in terms of a designing a “Quality System” rather than a single quality process or a series of quality checks. A quality system provides a framework for analyzing your project and focuses on early detection of issues.  
  • Involving your clinical quality assurance (CQA) team. Considering you are building a Quality System, consider involving your CQA team as part of the formal process. Trained in Quality Management Systems and armed with the concepts needed to execute, they can be a valuable partner.  
  • Implementing and training on approved corporate-wide policies and procedures governing quality processes in clinical trials.
  • Placing adequate focus on outsourcing and/or trial oversight. These are likely to be vulnerable areas and can create blind spots for sponsors. CROs will benefit from also considering how to build transparency in the process for their sponsors.  
  • Proceeding with caution with new technology solutions.  New technology solutions are growing and abundant and their potential to improve processes is undeniable, but they can add complexity and present unknown or unforeseen risks.  
  • Tending to your electronic trial master file (eTMF). Your eTMF will become the area where your quality is “assessed” by regulatory bodies. Neglect this process and the corresponding appropriate documentation (e.g., a TMF Plan) at your own risk. See our webinar regarding good eTMF practices for sponsor and CRO coordination. 

Yes, this revision will provide some clarity to the expectations of regulatory bodies, but it doesn’t change the fundamentals. Clinical trials need to be scientifically sound, subject to objective review, and ensure participants are safe and well-informed. The focus on quality in the revision will support all of these objectives.  If implemented thoughtfully, ICH E6(R3) can allow sponsors and CROs to create meaningful and powerful efficiencies in the process and improve the safety and reliability of results.   

If you would like to discuss or learn more about how DZS can help implement these ideas on your next trial, contact us at www.DZS.com