Collaborative partners and participants in the clinical trials ecosystem are concerned that the current model for conducting trials is unaffordable, unsustainable, and may hinder the generation of reliable evidence. To address this inefficiency, improvements in protocol design, trial planning, and quality oversight are essential.

CTTI identified the need to apply Quality by Design (QbD) methods to clinical trials while working on improving monitoring procedures. The CTTI Monitoring Project concluded that clinical trial monitoring should be part of an overall quality framework. Participants from various sectors of the clinical trials ecosystem agreed that adopting the QbD approach for trial planning, conduct, and oversight is crucial for ensuring trial quality and efficiency. However, there was limited information available on how to apply QbD principles to clinical trial design.

• The Monitoring Project: “Effective and Efficient Monitoring as a Component of Quality Assurance in the Conduct of Clinical Trials” (2009-2011)
• Quality by Design (QbD): “Workshops on Quality by Design (QbD) and Quality Risk Management (QRM) in Clinical Trials” (2011-2015)
• Quality by Design (QbD) Adoption (2018-2020)

• Develop broad principles for Quality by Design (QbD) that can be applied across all clinical trials.
• Offer hands-on opportunities for collaborative partners involved in clinical trial development, implementation, and oversight to put QbD principles into practice.
• Identify ways to share the agreed principles and promising approaches from the workshops.

• Utilizing the QbD toolkit from the beginning of a trial will help minimize significant errors, enhance the trial's overall integrity, and increase participant safety and the credibility of the results.
• Concentrating on critical aspects of a trial, such as the critical-to-quality factors (CQFs) outlined in the Principles Document, will improve trial efficiency and significantly reduce the burden on sponsors by alleviating the perceived need to address every potential risk.

• Literature review
• Electronic survey
• Expert meetings and workshops
  • Workshop on Quality Risk Management, January 29-­30, 2014
  • Workshop on Quality Risk Management, January 28-29, 2013
  • Workshop on Quality Risk Management, September 20-21, 2012
  • Workshop on Quality Risk Management, August 23-24, 2011
  • Expert Meeting on Monitoring, October 13-14, 2010
  • Expert Meeting on Monitoring, November 4, 2009
• Qualitative interviews
• Review of FDA warning letters

CTTI's investigation into monitoring practices across sponsor companies revealed significant variability, with choices often not based on empirical evidence. Experts agreed that the main objectives of monitoring practices are to ensure patient safety, accurately represent key data, comply with the protocol, and improve trial quality. Monitoring is most effective when it can identify errors early, allowing for corrective training to address issues, and should be tailored to the specific needs of a trial. Risk-based monitoring was suggested as a more effective alternative.

During the investigation and analysis of monitoring practices, it became clear that additional factors contribute to trial quality and efficiency. An expert working group recommended convening a follow-on Quality by Design (QbD) Project. QbD aims to build quality into the scientific and operational design of clinical trials from the outset, preventing important errors rather than remediating them after the fact, and ensuring trials are feasible to conduct. Through evidence-gathering activities, CTTI identified critical-to-quality (CTQ) factors in its Principles Document, including:

• Protocol design
• Feasibility
• Patient safety
• Study conduct
• Study reporting
• Third-party engagement

In addition to these factors, the project recommended practices that contribute to the successful application of QbD principles in clinical trials, such as:

• Creating a culture that values and rewards critical thinking and open dialogue about quality, beyond just relying on tools and checklists
• Focusing efforts on activities essential to the credibility of study outcomes
• Involving a broad range of those with vested interest in protocol development and discussions around study quality
• Prospectively identifying and periodically reviewing the critical-to-quality factors

CTTI provided examples of successful application of these principles in the QbD Webinar Series and offered guidance on implementing QbD in clinical trials through the QbD Toolkit.

• Reflection paper on risk-based quality management in clinical trials by the EMA, September 2013
• Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring by the FDA, August 2013

Organization affiliations are listed as active affiliations during the project.

*Indicates former project manager, team leader, or team member.