Defining QTLs: A Must-Do Step in the Trial Design Process

Within the bounds of risk-based quality management, the utilization of predefined Quality Tolerance Limits (QTLs) is a way to control quality and risk in clinical trials. As outlined by ICH E6(R2), a QTL is a level, threshold, or value associated with a parameter that is critical to quality.

Quality in clinical trials may be defined as the absence of errors that matter. [CTTI QbD Project]

At study level, QTLs proactively control systematic risk to factors that are critical to quality. In clinical trials, these so-called Critical to Quality factors (CtQ factors) have the potential to impact patient safety, data integrity, and/or the validity of trial results. In general, critical to quality factors function as communication vehicles to ensure quality alignment across the study.

Examples of commonly used CtQ factors are:

  • Primary objective
  • Safety objectives
  • Subjects’ eligibility
  • Investigational product exposure[1]

ICH E8(R1) General Considerations for Clinical Studies (draft version) describes CtQ factors as relevant to ensuring study quality. The integrity of these factors is crucial. If their integrity is undermined by errors of design or conduct, the reliability or ethics of decision-making is directly affected. Ideally, CtQ factors should already be identified for a project but at least for each study at the time of protocol design. QTLs – as trial-level parameters – should be established at the planning stage of a clinical trial, i.e. prior to trial initiation.

QTLs must be based on:

  • Medical and statistical expertise of similar trials
  • Historical data collected from similar studies
  • Statistical methods and modeling

TransCelerate recommends establishing a limited number of important parameters (for example, 3 to 5)[2].

Since the nature of a QTL is to identify systematic risks to patients and data integrity at the trial level, the following 7 most commonly used QTLs are applicable to almost all studies irrespective of the area:

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3. Risk-based quality management: quality tolerance limits and risk reporting. TransCelerate website. Published 2017. Accessed 20 Jan 2021.

4. MacDonald С., Article: New ICH Guidelines Address Industry Inefficiency. Accessed 20 Jan 2021.