Using Quality Tolerance Limits in Clinical Trials

Clinical trials are a crucial step in the development of new drugs and treatments, and it’s essential to ensure their safety and reliability. The recent update to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6(R2) has introduced predefined quality tolerance limits (QTLs) to help identify systematic issues that can impact subject safety or the reliability of trial results. In this post, we will focus on the approach to dealing with loss of evaluable subjects, patient discontinuation, and inclusion/exclusion errors.

ICH guideline

The International Council for Harmonisation (ICH) has introduced a new guideline, ICH E6(R2), which modernizes quality control in clinical trials. This guideline introduces Quality Tolerance Limits (QTLs) as a way to provide feedback on clinical trial parameters, elevating these measures to the Quality Management System (QMS) and providing greater visibility across clinical trial functions and the enterprise.

By using QTLs as a part of the quality control process, the industry can ensure that clinical trials are conducted with the highest level of participant protection and trial result reliability. The QTL Framework provides a roadmap for industry sponsors and their agents to follow in order to effectively implement QTLs in their clinical trials.

The QTL Framework introduced by TransCelerate aims to improve the quality of clinical research and to protect trial participants and the reliability of trial results. The framework is intended to maximize efficiency and minimize confusion in the implementation of QTLs. The framework includes proposed approaches for implementing QTLs for a clinical trial as defined in ICH E6(R2) and considerations for setting thresholds. The goal of the framework is to minimize confusion and maximize efficiency in the implementation of QTLs. The QTL process consists of three stages: Define, Monitor, and Report.

The Define stage, which occurs after the availability of a draft protocol and before enrollment of the first participant, includes defining the parameters and thresholds for QTLs and developing a QTL monitoring plan to define the timeframe and frequency of reviews and data sources for monitoring.

The Monitor stage, while the clinical trial is ongoing, calls for periodic reporting according to the monitoring approach. If there are any QTL deviations from the predefined thresholds, they would be investigated and corrected as needed.

The Report stage, after the trial ends, includes generating a summary report of QTL deviations and associated preventive and/or corrective actions. The highlights or important QTL deviations and actions would also be included in the clinical study report.

Implementation that we know about

QTLs are a statistical process control methodology that facilitates the execution of high-quality clinical trials. Although the ICH guidelines provide a sparse definition of QTLs, they are a requirement for all trials. TransCelerate has published guidance on how to interpret QTLs, and Pfizer defines them as a limit that defines when a trial may be in danger of having reduced validity.

The study teams are responsible for setting the QTLs and should consider the medical and statistical characteristics of the variables as well as the statistical design of the trial. There is often confusion between the difference between key risk indicators (KRIs) and QTLs. KRIs monitor similar parameters to QTLs, such as dropout rate, but are at the site-level. QTLs are at the trial-level and intended to assess the quality of an entire trial.

What is TransCelerate?

It is a non-profit organization focused on advancing innovation in life sciences research. It was founded by leading pharmaceutical companies in 2012 to increase efficiency and improve the quality of clinical research. One of the initiatives of TransCelerate is the development of a Quality Tolerance Limits (QTL) Framework to support the industry in implementing QTLs as required. The framework includes proposed approaches for implementing QTLs for a clinical trial and considerations for setting thresholds.

The implementation of QTLs according to the framework is consistent with ICH E6 and industry best practice for measuring and monitoring clinical trial quality. The framework is intended to maximize efficiency and minimize confusion in the implementation of QTLs and provide greater visibility of important indicators of participant protection and trial result reliability across clinical trial functions and the enterprise.

In conclusion

The introduction of QTLs by the ICH E6(R2) guidelines and the development of the QTL Framework by TransCelerate have modernized quality control for clinical trials. By providing a comprehensive and efficient approach to implementing QTLs, the framework supports the industry in improving the quality of clinical research and protecting trial participants and the reliability of trial results.