Why everyone involved in clinical research should read the revision of ICH E8

In the shadow of the new European Clinical Trial Regulation, which finally entered into application on 31 January 2022, revision 1 (R1) of ICH Guideline E8 on general considerations for clinical studies was adopted by the (global) Regulatory Members of the ICH Assembly on 06 October 2021.

While everyone working in clinical research is probably very familiar with Efficacy Guideline ICH E6 or Good Clinical Practice, ICH E8 may be less well known, even though it is basically the “parent” document of all clinical trial-related ICH Guidelines. Check the original version that is almost 25 years old and you will recognise the general principles and methodology of clinical development, including the phased clinical trial approach we have been using for many years.

ICH E8 (R1) is an important step forward in the renovation of GCP that was announced by the ICH in 2017. The guideline builds on the risk-based quality approach that was incorporated in the in 2016 adopted revision 2 of ICH E6 and puts emphasis on bringing quality not only in the conduct, but also in the design of a clinical study.

I believe that for everyone who is aiming for quality beyond compliance in clinical development, the revised guideline is an interesting and refreshing read. It gives space to an open dialogue and critical thinking, and it forms a good basis for the expected flexibility in the next revision of ICH E6 Good Clinical Practice.  

Three takeaways from ICH E8 (R1), which I would like to highlight:

1. Invest upfront and save at the backend

The EMA already mentioned in 2013 that “there are too many trials in which avoidable quality problems arise” and that this and the extensive costs of clinical study oversight “strongly suggests that [the] current approach to clinical quality management is in need of review and reorientation”.

Based on first-hand experience, I am tempted to say this statement is still relevant. Fortunately, I have seen more and more companies investing resources in innovative quality management approaches, where a retrospective ‘quality by testing’ approach (i.e. through quality checks after the fact) has largely been replaced by a proactive ‘quality by design’. ICH E8 (R1) explicitly promotes quality by design.

Quality by design requires an investment upfront: first in setting up the systems and creating awareness, and then in extra time and resources, even before the study starts. However, when it is finally part of the company’s quality culture, I am convinced that everyone will prefer this collaborative, risk-based, “first time right” (and thus in the end time-saving) approach to clinical research. After all, I cannot imagine that there are many people who enjoy spending a lot of time on investigating, explaining and correcting what went wrong.

2. There is no “one size fits all”

Although a quality management system with standard operating procedures may give you the impression that conducting a clinical study could be a routine exercise: It is far from that. Standardisation in processes will certainly help to ensure regulatory compliance. However, ICH E8 (R1) makes clear that an open dialogue, critical thinking and a risk-based focus on what is critical to quality, can facilitate proactive and adaptive, efficient and effective, innovative approaches to quality in clinical research.

3. Break down the silos

Although not so explicitly mentioned in ICH E8 (R1), it is essential to realise that a clinical study should in fact be seen as a system. To let this system run smoothly, it is important that no radar is blocked, parties and departments do not work in isolation, and that all players acknowledge the importance of their role in ensuring the quality of a study.

Collaboration and communication are key. As was also emphasized during the MHRA GCP Symposium in March 2022, a reliable scientific and operational study design requires a “proactive, prospective, multidisciplinary approach” (quoting Miah Jung (FDA)), in which all professional players, the Sponsor, CROs, vendors and investigators, become involved in an early stage and continue to communicate throughout a study.

Finally, ICH E8 (R1) gives the patient a central role. In ICH E6 (R2) GCP the trial participant is still referred to as a passive “subject”. However, when you want your study program to be valuable, you will need to talk with the individuals for whom it is designed. In short, place patients and/or patient organisations in the heart of the system called clinical development and let them be heard.

The revision of ICH E8 has been adopted by the CHMP (Committee for Medicinal Products for Human Use) of the European Medicines Agency on 14 October 2021 and will become effective in EU Member States on 14 April 2022. Link to ICH E8 (R1): ICH guideline E8(R1) on general considerations for clinical studies (europa.eu). 

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