In our previous articles, we committed to demystifying the “HOW” of implementing Risk-Based Quality Management (RBQM). Today, we begin with the starting point of that framework: the identification of Critical to Quality Factors (CTQFs).

What Regulators Expect: Designing Quality into Clinical Trials

The final ICH E6(R3) guideline marks a significant evolution in how quality is defined and implemented in clinical research. It shifts away from retrospective quality control toward a proactive, quality-by-design (QbD) approach.

As articulated in ICH E6(R3), Principle 6, the quality of a clinical trial is defined as:

Fitness for purpose

This concept establishes that trial quality is determined by how well the design and conduct of the study support its scientific objectives and protect participant rights and safety.

Critically, the same principle emphasizes:

Factors critical to the quality of the trial should be identified prospectively

In practice, this means that quality must be proactively embedded into both the scientific and operational aspects of trial planning, not assessed retrospectively through inspection alone. The early identification of CTQFsis therefore fundamental to designing trials that are not only operationally feasible, but also robust, and credible.

These CTQFs are the trial attributes that are fundamental to:

• Protecting the rights, safety, and well-being of participants,
• Ensuring the reliability and interpretability of trial results,
• Supporting scientifically sound and ethically decisions based on trial results.

These regulatory expectations are rooted in ICH E8(R1), which introduces CTQFs as the basis for quality-by-design planning.

Quality cannot be reconstructed; it must be built in from the start

From Guiding Principles to Practical Action: The Role of CTTI

While ICH guidelines define the “what”, the Clinical Trials Transformation Initiative (CTTI) offered essential support in understanding the “how”. The 2015 CTTI Critical to Quality Factors Principles Document, part of its Quality by Design project, defined quality as:

“The absence of errors that matter.”

Here, “errors that matter” are those that materially affect participant safety or the credibility of trial results.

The CTTI document encouraged proactive, cross-functional discussions early in trial design to:

1. Identify which aspects of the study are truly critical to quality;
2. Determine what strategies and actions will effectively and efficiently support those aspects.

Rather than prescribing specific CTQFs, the CTTI framework offers six high-level categories to help guide study teams in identifying what is critical to quality within their specific trial context:

1. Protocol Design
2. Feasibility
3. Patient Safety
4. Study Conduct
5. Study Reporting
6. Third-Party Engagement

Each category is further broken down into subcategories or key areas of consideration, which provide more targeted prompts. For example, under Protocol Design, subcategories include for instance endpoints, stratification methods, eligibility criteria.

⚠️ These are not CTQFs themselves. They are areas where CTQFs may emerge depending on the context, design, and objectives of the trial.

Each area should be explored systematically to identify trial-specific factors that, if compromised, could significantly impact participant protection or data quality.

At Qlarix, we have applied this framework as the foundation for the development of a configurable CTQF model within our risk-based quality management software – WiseCLIN. This type of practical application demonstrates how CTTI’s guidance can be transformed into repeatable, fit-for-purpose workflows that meet both regulatory expectations and operational realities.

What Does This Look Like in Practice?

Critical to Quality Factors (CTQFs) must be specific, contextual, and actionable.

To illustrate this, the following example show what qualifies as a CTQF and what does not The CTQF is also categorized according to one of the six high-level areas identified by the CTTI.

🫀 Cardiovascular Outcomes Trial

• Context: Phase III trial evaluating a lipid-lowering agent’s effect on major adverse cardiovascular events (MACE).
• CTQF Category: Protocol Design.
• CTQF: Reliable capture of survival status for all participants at study end.
• Why it’s critical: This data directly impacts the primary endpoint. Missing survival information undermines endpoint integrity.
• Not a CTQF: Source verification of body temperature at routine visits. Low impact on participant safety or data integrity in this context.

Final Thoughts

CTQFs are not a checkbox. They are a mindset

By asking the right questions early and embedding the answers into study design, conduct, and oversight, we don’t just reduce risk. We build trials that are more resilient, more efficient, and more credible.

Because in the end, the success of a clinical trial doesn’t come from how many procedures we perform, but from how well we protect what’s critical.

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WiseCLIN is our purpose-built RBQM software designed to help sponsors implement risk based quality management in a structured, traceable, and inspection-ready way. Aligned with the principles of ICH E6(R3), WiseCLIN supports proactive RBQM by connecting risk identification, evaluation, mitigation, review, and oversight in one practical workflow.

Contact us here to learn more or request a demo.

Thank You,

Dr. Leire Zuñiga – PharmD PhD

Co-Founder and CQO, Qlarix | Founder and Managing Director, Pharmity | Risk-Based Quality Management (RBQM) Expert.

20+ years experience in Pharma, Biotech, CROs. Skilled in Quality Management, Good Clinical Practice and Computerised System Validation.

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