Stakeholders across the clinical trial enterprise have expressed concern that the current model for conducting trials is unaffordable and unsustainable, and potentially impedes the generation of reliable evidence. Overcoming this inefficiency rests on improving protocol design, trial planning, and quality oversight.

CTTI first recognized the need for applying QbD methods to clinical trials while working to improve monitoring procedures. A key conclusion of the CTTI Monitoring Project was that clinical trial monitoring should be viewed as one component of an overall quality framework. Project participants, representing a broad cross-section of the clinical trials enterprise, agreed that widespread adoption of the QbD approach to trial planning, conduct, and oversight was needed to ensure trial quality and efficiency; however little information was 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 Trial” (2011-2015)

• Develop broad principles for QbD applicable across clinical trials
• Provide hands-on opportunities for stakeholders involved in clinical trial development, implementation, and oversight to translate QbD principles into practice
• Identify mechanisms to disseminate agreed principles and promising approaches identified during the workshops to a broad array of stakeholders

• Using the QbD toolkit to build trial quality from the start will help minimize errors that matter and improve the overall integrity of the trial while increasing participant safety and credibility of results.
• Focusing on critical aspects (e.g., those critical to quality factors [CQFs] defined in the Principles Document) of a trial will improve trial efficiency and also substantially reduce the burden of clinical trial conduct by relieving sponsors of a perceived obligation to mitigate every potential risk posed by a trial.

• Literature review
• Electronic survey
• Expert meetings and workshops
  • CLICK HERE to view materials from the January 29-­30, 2014 Workshop on Quality Risk Management
  • CLICK HERE to view materials from the January 28-29, 2013 Workshop on Quality Risk Management
  • CLICK HERE to view materials from the September 20–21, 2012 Workshop on Quality Risk Management
  • CLICK HERE to view materials from the August 23-24, 2011 Workshop on Quality Risk Management
  • CLICK HERE to view materials from the October 13 - 14, 2010 Expert Meeting on Monitoring
  • CLICK HERE to view materials from the November 4, 2009 Expert Meeting on Monitoring
• Qualitative Interviews

CTTI’s investigation of monitoring practices across sponsor companies found that practices vary widely and that choice of monitoring practices was often not based on empirical evidence. Experts agreed that the main objectives of monitoring practices were to ensure patient safety, represent key data accurately, comply with the protocol, and improve trial quality. Because monitoring is most effective when it can identify errors early so that corrective training can address issues, and should be tailored to the needs of a particular trial, risk-based monitoring was suggested as a more effective alternative.

During the investigation of monitoring practices and analyses of results, it became apparent that additional factors contribute to trial quality and efficiency. An expert working group suggested convening a follow-on Quality by Design (QbD) Project. QbD employs an approach to prospectively build quality into the scientific and operational design of clinical trials, such that important errors are prevented rather than remediated after the fact, and trials are feasible to conduct. Through evidence-gathering activities, CTTI described those factors that are “critical to quality” [CTQ] in CTTI’s Principles Document and include the following:

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

In addition to the factors mentioned above, the project recommended additional practices that contribute to successful application of QbD principles to clinical trials, including:

• Creating a culture that values and rewards critical thinking and open dialogue about quality, and that goes beyond sole reliance on tools and checklists;
• Focusing effort on activities that are essential to the credibility of the study outcomes;
• Involving the broad range of stakeholders in protocol development and discussions around study quality; and
• 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 guidance on how to implement QbD in clinical trials in 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