The Evolution of Clinical Quality: Key Considerations from ICH E6 R3

The International Council for Harmonisation (ICH) good clinical practice (GCP) guidelines are critical in ensuring the safety and rights of clinical trial participants. The guidelines also facilitated international harmonization of clinical research making it easier to conduct multi-national trials and bring new therapies to market more efficiently.

The Council was first formed in 1990 with the goal of harmonizing regulatory requirements across Europe, Japan, and the United States. The first guidelines published in 1996 and known as ICH GCP E6 provided guidance on the design, conduct, and reporting of clinical trials. ICH GCP R2 was subsequently published in 2016 and expanded on steps to ensure data integrity, encourage risk-based monitoring, and address the use of electronic records and signatures.

Updates to R3

Now, ICH GCP E6 R3 introduces quality by design, further refines risk management, and establishes clearer roles and responsibilities. The transition from R2 to R3 represents a significant evolution in the ICH guidelines – there are some key elements for sponsor organizations to focus on as they optimize clinical quality.

Quality by Design

R3 builds on the quality by design framework, introduced in ICH GCP R8. This framework encourages the implementation of quality assurance throughout the clinical trial lifecycle. Principle 6 of R3 expands on the identification and implementation of critical to quality (CtQ) factors – attributes vital to the protection of subjects and the integrity of the data collected. The guidelines encourage the strategic use of CtQ factors to detect and address deviations from GCP, as well as the protocol and regulatory requirements so that recurrence is prevented. Ultimately trial participant safety and data integrity is maintained.

Risk Proportionality

Risk management is further streamlined in R3, focusing on tailoring trial processes proportional to the risks they pose to subjects as well as critical data. Risks to CtQs factors should be proactively managed and risk language/monitoring adjusted according to new and changing information during the clinical trial. Furthermore, systems and processes capturing, managing, and analyzing data need to be fit for purpose, capturing data required by the protocol and should address key risks to subjects and data integrity.

Trial Design

The importance of robust and risk-based trial design is a key element of R3. Emphasis should be placed on creating operationally sound processes and avoiding unnecessary complexity, procedures, and data collection. This all starts with a well-designed clinical protocol, in addition to trial plans and documents aiding in protocol execution. Trial processes should also be optimized to focus on the key objectives and quality and risk management elements should be put in place. Sponsors should ensure a diverse multidisciplinary team of stakeholders supports the design of the study and the clinical development plan. Lastly, computerized systems used in the capture of data should be fit for purpose and support the CtQ factors.

As trial designs and clinical technologies become increasingly complex, sponsors must prioritize patient safety and data integrity more than ever. R3 acknowledges no clinical trial can be flawless, but it encourages organizations to adapt their processes and systems to address the most critical risks effectively. By embracing this proactive approach, organizations can continue to drive innovation while upholding the highest standards of clinical research and patient care and can more effectively bring world-class treatments to market.

Back to Resources