Quality by Design in Clinical Trials

Successful clinical trials are undoubtedly the result of a well-implemented Quality Management System (QMS), and integrating Quality by Design in clinical trials ensures that this system goes beyond merely fulfilling regulatory requirements. Incorporating a proactive approach like Quality by Design (QbD) while configuring a QMS structure for clinical trials raises the probability of risk management rather than response-based problem-solving.

Applying QbD in QMS is like building a house with a strong, solid foundation and shielding it from damage and repairs.

The idea of integrating the concept of Quality by Design right at the outset in the QMS skeleton not only reduces the associated risks but also amplifies the other vital aspects of clinical trials, such as patient safety, data integrity, and reliability of trial outcomes. By embedding QbD principles into the very foundation of a Quality Management System, organizations can proactively address variability and ensure consistent quality throughout the trial lifecycle.

To explore this transformative approach, four key considerations are outlined below:

Fundamental principles of QbD
Driving excellence in quality
Regulatory expectations
Getting past the roadblocks

Let us now explore each of these aspects in greater detail.

1. Fundamental principles of quality by design in clinical trials

The fundamental principles of QbD in clinical trials include a thorough understanding of the trial process, identification of critical to quality (CTQ) factors, proactive risk management, robust protocol design, and continuous improvement throughout the study lifecycle. Presented below is a point-wise breakdown and basic sketch of the fundamentals of QbD in clinical trials.

Critical-to-Quality (CTQ) factors
Quality Risk Management (QRM)
Quality Tolerance Limits (QTLs)
Continuous Quality Improvement (CQI)

1.1 Critical-to-quality (CTQ) factors

In order to enumerate the basic ingredients of Quality by Design in clinical trials, let us begin by acknowledging the Critical-to-Quality (CTQ) factors, which are hallmark features to secure trial outcomes. The concept of Critical-to-Quality (CTQ) focuses on identifying the specific aspects of a clinical trial that have the greatest impact on its overall quality. These are not just general quality measures, but key elements that are essential and often decisive in determining trial success.

Highlighted below are the most effective approaches in identifying and managing CTQ factors:

Define clear study objectives: Ensure the goals of the study are clearly stated and that the design and data collection align with these goals.
Involve stakeholders early: Engage all relevant stakeholders at the beginning of the study planning process to help shape the study design and improve decision-making.
Use the protocol to highlight CTQ factors: Draft protocols that reduce unnecessary complexity, eliminate redundant procedures and data collection, and focus on CTQ elements that directly impact trial quality.
Identify training needs early: Determine the required skills for each role and ensure appropriate training is provided to study personnel from the start.
Communicate study outcomes effectively: Ensure results are shared in a way that is comprehensive, accurate, and timely.

1.2 Quality risk management (QRM)

Spotting potential risks early on in a clinical trial reduces the chance of inaccurate results, speeds up the overall drug development process from discovery to delivery. QRM must formally be included as part of the Quality Management System (QMS). Risk management systems should be designed to point out risks before they turn into stumbling blocks. This can be pulled off by considering the following points:

Regular QRM Meetings: Conduct periodic meetings with relevant stakeholders to review identified risks, recommend appropriate mitigation strategies, and break down and control risks to an acceptable level.
Benchmarking: Comparing data with similar studies
Stakeholder discussions: Gathering diverse insights and opinions
Trend analysis: Monitoring recurring patterns or anomalies
Reviewing safety alerts and investigation recommendations
Centralized monitoring: Using remote oversight systems
Remote data analysis: Identifying risks without on-site visits
Strategic on-site visits: Prioritising site monitoring based on risk level

1.3 Quality tolerance limits (QTLs)

Quality Tolerance Limits (QTLs) are pre-set thresholds for critical-to-quality data
in clinical trials. When these limits are surpassed, systems must automatically trigger corrective and preventive actions to maintain trial integrity and participant safety. Regulatory bodies like the FDA and EMA emphasize the importance of QTLs in ensuring high-quality trial outcomes. All deviations and subsequent corrective measures must be documented in clinical study reports as per ICH-E6 R2 guidelines. The following suggestions can be taken into account while defining QTLs:

Identify which parameters need QTLs and set their threshold levels
Develop clear action plans for when QTLs are exceeded
Create a detailed method for establishing thresholds
Define timelines for ongoing monitoring and review of QTLs

The U.S. FDA and EMA, either of them emphasize the positive impact of Quality Tolerance Limits (QTLs) in clinical trials. The U.S. FDA aligns its approach with ICH E6(R2), while the EMA requires QTLs to be applied to key study parameters. Both regulatory bodies expect sponsors to establish and monitor QTLs with foresight for critical data and processes, and to investigate any deviations that exceed these limits.

1.4 Continuous quality improvement (CQI)

Continuous Quality Improvement, as the name implies, covers constant review and process improvement uninterruptedly throughout the trial. Diverse approaches to execute CQI may comprise a series of actions such as:

Standardizing process, escorted by means of well-documented SOPs, with consistency across sites
Updating them at regular intervals in accordance with changing practices
Protocol amendments
Training and retraining then and there. In a different light, training the study personnel on the fundamentals of QbD with an emphasis on CTQs and risk management strategies is another approach to CQI. Training may also include continuous training on GCP and SOPs.
Setting Key Performance Indicators (KPIs) and metrics for quality and reviewing them periodically in quality review sessions is yet another favorable approach towards CQI.

2. Driving excellence in quality: QbD Implementation in QMS

Consolidating a traditional QMS with QbD strengthens the system and reinforces quality from the start of a clinical trial rather than just evaluating it at the end. Here’s how QbD strengthens QMS by using core concepts stated earlier:

Critical-to-Quality (CTQ) factors are identified early and built into the protocol.
Quality Risk Management (QRM) methods help find and reduce risks before they become serious.
Quality Tolerance Limits (QTLs) trigger immediate action when important data fall outside acceptable ranges.
Supports proactive Quality Control
Focuses on audits and reviews on high-risk areas
Encourages early corrections and preventive steps
Helps meet regulatory expectations more easily
Improves trial outcomes with:
- Fewer protocol deviations
- More predictable timelines
- Faster issue resolution
- Better audit readiness and data quality

Value-added benefits of a QbD approach to QMS

Creates patient-centered trials: Designs are more practical and focused on patient needs
Enables smarter monitoring: Risk-based monitoring helps prioritise key areas and manage resources efficiently
Encourages team collaboration: QbD promotes teamwork across departments like clinical operations, data management, biostatistics, and Quality Assurance (QA). This improves communication and coordination throughout the trial.

Looking for support in protocol writing and incorporating the quality aspects into it? Click here to learn.

3. Regulatory expectations and global guidelines in quality by design in clinical trials

International regulatory bodies strongly support the use of Quality by Design (QbD) in clinical trials. Several global guidelines emphasize the importance of building quality into the design, execution, and monitoring of studies to protect participants and ensure reliable data.

ICH-E8 (R1) Guideline: General Considerations for Clinical Studies focuses on designing quality into clinical studies from the start. The sections on study design, conduct, and reporting highlight the importance of planning for quality. Sponsors are expected to identify Critical-to-Quality (CTQ) factors that impact participant safety and data credibility.
The modules on Quality Management and Monitoring in ICH-E6 (R2) Good Clinical Practice (GCP) Guideline emphasize QRM as part of a QMS. Sponsors are expected to channel resources to the highest-risk areas, especially those affecting safety and data integrity.
The US FDA’s Guidance on A Risk-Based Approach to Monitoring of Clinical Investigations encourages using QbD to improve trial quality and oversight. Based on the guideline, sponsors are expected to show a clear understanding and control of trial processes to effectively limit potential risks.
European Medicines Agency (EMA) Reflection on Risk-Based Quality Management (RBQM) recommends applying risk-based methods across all stages of a trial. It encourages the use of QbD principles to improve trial management and expects sponsors to use risk assessments to help decide on where to focus monitoring and quality control efforts.

Want to learn more about regulatory expectations and global guidelines in QbD in clinical trials? Contact our experts.

4. Getting past the roadblocks: Practical & structural hurdles

The QbD concepts being more contemporary than conventional manifest with a lack of awareness and understanding among stakeholders, due to partial familiarity with these concepts in a clinical setting. In exchange for resistance to change, collaborative training on CTQ factors, risk-based approaches, and regulatory expectations provides a way forward to prevent superficial implementation of these emerging concepts.

Customary clinical trial teams often rely on reactive quality checks, such as monitoring deviations, rather than embracing proactive, design-based approaches. This mindset fosters continued dependence on established practices and creates reluctance to adopt risk-based, progressive approaches. Handling this challenge requires strong leadership, effective communication, and robust change management strategies to facilitate the transition.

Limited resources and time pressures can make QbD seem resource-intensive and time-consuming during the early stages of trial implementation. This concern may consequently result in less emphasis on QbD planning activities. To encourage adoption of these novel techniques, it is important to clearly communicate the long-term benefits of QbD, such as fewer protocol amendments, improved data quality, and reduced monitoring costs.

Barriers to articulating CTQ factors often stem from limited experience in identifying and prioritising key elements that influence trial quality. This may lead to risk-based approaches that are vague or unfocused, reducing the effectiveness of monitoring and controls. To address this, harnessing data from previous, comparable clinical trials to identify recurring patterns in critical quality attributes, risks, and operational issues is a practical option. Additionally, developing or adopting trial-specific CTQ monitoring checklists and uniform templates works as an alternative to ensure consistency and alignment in the identification and management of CTQ factors across study teams and sites.

Conclusion

Quality by Design (QbD) is revamping how clinical trials are planned and executed, instilling quality as a foundation in the end-to-end process, thus leading to stronger trial design and execution. With global regulatory bodies endorsing risk-based, evidence-driven approaches, QbD is fast becoming essential to effective Quality Management Systems (QMS). While challenges like fragmented workflows and uncertainties in defining CTQs persist, they can be addressed through well-defined risk assessment tools, interdisciplinary teamwork, and a resolve to continuous improvement. A QbD-based QMS not only supports innovation but also builds stakeholder confidence and long-term success.

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