By Kimberley Hacquoil, Exploristics CDSO
Earlier this year, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released a draft revision to their most widely recognised E6 guideline (ICH E6(R3)). The overarching purpose of the guidance is to provide a comprehensive framework for planning, conducting, and reporting clinical trials whilst maintaining ethical and scientific rigor. It underscores the importance of ensuring the credibility, reliability, and integrity of clinical trial data for regulatory decision-making and safeguarding the well-being of trial participants. But what are the changes and how might this impact the future designs of clinical trials?
Key changes in the guideline concerning trial design
The proposed modifications aim to make the guideline more flexible, evidence-based, and aligned with modern trial designs and data sources.
- Increased emphasis on Clinical Trial Design
Appropriate clinical trial design is highlighted to ensure that trial objectives are met, and that data generated are reliable and robust. There is a shift to include greater flexibility in the conduct of clinical trials, allowing for innovative trial designs and methodologies, and the use of innovative digital health technologies to keep clinical trials in line with advancing technologies to facilitate enrolment, retention, data capture/monitoring and analysis.
- Encouraged focus on fit-for-purpose approaches
The concept of Quality by Design, including critical-to-quality factors, is incorporated to prevent errors that could affect trial results. Risk-based methods are supported in various aspects of clinical trials, such as design, conduct, oversight, recording, and reporting. These approaches should be proportionate to the level of risk and importance associated within the trial. This means data does not have to be error-free if it still supports conclusions equivalent to those from error-free data.
- Incorporated learnings from innovative clinical trial designs and lessons from public health emergencies/pandemics
Decentralized trials are now addressed in the guidelines, including the acceptability of remote consent, data acquisition tools, home nurses, and secure remote monitoring and audit. There’s also an emphasis on public involvement and trial diversity, requiring sponsors to describe the rationale for participant inclusion/exclusion to improve trial generalizability.
- Enhanced patient centricity
Patient perspectives are given more importance in the design and conduct of clinical trials. Clear communication, privacy protection, and minimizing participant burden are highlighted. As well as thinking more about how digital technology solutions can be utilised to reduce requirements for patients.
- Spotlight on data quality
There is now strong emphasis on implementing a Quality Management System (QMS) to maintain the quality of clinical trials, including risk management, monitoring, and continuous improvement. The guideline underscores the significance of data quality and integrity, emphasizing the need for robust systems to ensure these aspects including utilisation of electronic systems and data again reflecting advancements in technology. “Data reliability” is introduced as a concept, highlighting the trustworthiness of trial data. The guideline provides guidance on ensuring data reliability through validated systems, regular data review, and anomaly management.
What might be the impact of these changes for those who design clinical trials?
- Greater engagement with statisticians
It will be important for clinical teams to work even closer with statisticians at the design stage to ensure the revised ICH principles are incorporated effectively. This will include integration of the quality by design methods to identify and quantify the impact of potential risks to data integrity as well as strategies to mitigate these. With more focus on risk-based approaches to trial design, statisticians are well placed to communicate effectively to key stakeholders to ensure risks are well understood and managed appropriately.
- Thinking prospectively about trial diversity
With attention on trial diversity and its importance to address this in a proactive manner, study and project teams may need to explore this at the design stage. This may include considerations of different inclusion/exclusion criteria, sub-group analyses and the generalisability of trial results to different demographic groups – it’s too late to consider this when the study is completed!
- Earlier consideration of data collection and integrity
Data collection and integrity need to be considered at the design stages to protect the study from unnecessary failure. Poorly designed studies which do not fully consider the impact of this, both in terms of data capture and statistical analysis plans, can leave the project team unable to make robust and clear decisions throughout or at the end of a study. Exploring different data capture options, uncertainties surrounding quality of the data and analysis choices to reduce bias are all vital to enable teams to put plans in place to reduce the impact on study integrity and results. Again, doing this in a prospective way is imperative.
- Building patient needs into study design
With a focus on patient-centricity, clinical teams need to prioritise the needs and perspectives of participants in the trials. This will include aspects related to the number and types of assessments that are carried out on participants. Investigating different options and the impact on trials results for repeated measurements or which endpoints are collected will ensure studies are designed with participants well-being in mind and reduce unnecessary burden with little or no reward to inform decisions at the end of the trial.
Working towards more efficient and higher quality clinical trials
Overall, the impact of ICH E6(R3) changes is expected to empower clinical teams and lead to more efficient, adaptable, and high-quality clinical trials. It should also reduce unnecessary administrative burdens while maintaining a strong focus on patient safety and data integrity. As ever, the precise impact will depend on how these guidelines are implemented and adopted by stakeholders in the clinical trial ecosystem. Nevertheless, this update highlights a tangible way forward for developers seeking greater clinical trial success by improving current clinical design approaches.
The draft guidance is currently open for public consultation and the ICH expects to finalize the guideline by the end of 2023. Find out more below.
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