“Predefined quality tolerance limits” were introduced to ICH GCP in revision 2 of ICH E6 in 2016. They are mentioned in two paragraphs but with no guidance on how to define or use them. We know from MCC meetings and at the recent MCC Summit, where a working group discussed quality tolerance limits (QTLs) in detail, that many organizations are struggling to implement them. Indeed, over one third of MCC Summit working group participants said they do not currently even use QTLs. We have also had discussions that show many in the industry are confused with the concept and the terminology. For example, a QTL is a threshold level of a measurement parameter but the term is often used to describe the measurement rather than the threshold.
Current Body of Knowledge
In an effort to develop an understanding about QTLs, industry stakeholders are working together to define terms and develop approaches to implementing QTLs. A multi-stakeholder group at MCC – the Centralized Monitoring Community of Practice (CoP) – has been exploring the topic for several years and TransCelerate Biopharma, Inc published a paper on the topic September 2020. However, there remain many outstanding questions that organizations find challenging. For example:
- Can you have study-level KRIs (and general study-level risk and operational/performance monitoring) separate from QTLs?
- What constitutes an “important deviation” of a QTL (i.e., those that require reporting in the Clinical Study Report)?
- How does the use of leading versus lagging metrics impact the effectiveness of QTL parameters? For more information see MCC white paper “Measure the Right Things at the Right Time: Design KRIs and KPIs that Provide Timely Insights During Study Conduct” for details.
- How/when should QTLs be identified for a study (e.g., pre-study risk planning, QBD risk review, both, other)?
- Once you identify what QTL parameters you are going to track, how do you set the QTLs? When should QTLs be based on historical data/benchmarks, and when should they be based on “statistical characteristics of variables” (ICH E6 R2 language)?
- Can QTL thresholds be modified during a study?
MCC Forming Sub-Team to Explore QTL Topics and Develop Toolkit
MCC will convene a sub-team of industry Subject Matter Experts (SMEs) interested in working collaboratively to catalogue the questions and challenges organizations face with QTL implementation and create a QTL toolkit. MCC experts will lead the group through the process of developing a MCC QTL implementation toolkit that expands our understanding about QTLs, applies “measure the right things at the right time” concepts developed by MCC and assists organizations in implementation. The sub-team will report progress to the Centralized Monitoring Community of Practice on a regular basis. The work will culminate with the publication of an article in an industry journal.
One-hour online meetings, every two weeks at a time and day agreed upon by the sub-team. Meetings will begin in early December and run through June 2021.
- Summaries from MCC meetings on QTLs
- MCC white paper “Measure the Right Things at the Right Time: Design KRIs and KPIs that Provide Timely Insights During Study Conduct”
- Summary of the MCC Summit QTL Working Group discussions
- TransCelerate QTL Framework article
- Other inputs from sub-team members
- Step-by-step toolkit for implementation and use of QTLs
- Document summarizing the agreed approach to implementation and use – including exploring the questions above
- Article for publication in an industry journal
- Additional work needed by sub-team members – volunteers to draft and to review sections of the deliverables in between meetings
Contact MCC lead Keith Dorricott, if you are a SME and are interested in participating.
MCC Membership Information
This is a member-only group. For additional information about MCC membership options or to find out if your organization is a MCC member, please visit the MCC Membership webpage or contact MCC Director of Membership, Teresa Holland or call 317-622-0266.