Good Clinical Practice: A Question and Answer Guide2024/2025 Edition - 418

GCP: A Question & Answer Reference Guide
QTLs are of special significance because they are referenced in ICH E6 (R2) (as " predefined quality tolerance
limits " ) whereas KRIs are not. The guidance requires important deviations from the QTLs to be reported in the
Clinical Study Report:
5.0.7. Risk reporting
The sponsor should describe the quality management approach implemented in the trial and summarize
important deviations from the predefined quality tolerance limits and remedial actions taken in the
clinical study report (ICH E3, Section 9.6 Data Quality Assurance).
These brief references to QTLs have led to many debates, consortia and conference discussions, papers and
much confusion. A particular area of discussion has been over the relationship between QTLs and KRIs. KRIs
were already being used by early adopter organizations long before the introduction of QTLs to clinical trials in
2016. For example, a paper was published in 2011 entitled " A key risk indicator approach to central statistical
monitoring in multicentre clinical trials " in the journal Trials.
Some consider QTLs as being completely different to KRIs. Others define them as being focused at the trial
level with KRIs focused at the site level. More recently, a consensus has perhaps been growing as demonstrated by
a working group of early adopters of QTLs which was part of WCG Metrics Champion Consortium. It published
articles in Applied Clinical Trials in 2022 that described QTLs as being a subset of KRIs:
The parameters used to monitor QTLs and KRIs are metrics. QTLs are a special subset of KRIs that focus
on critical study risks.
And this view has been endorsed by more recent papers such as " QTL's Place in the QMS " published in
Therapeutic Innovation & Regulatory Science, March 2023:
We can then understand QTLs to be a designated subset of KRIs, focused on the most critical study-level
risks identified for a given clinical trial.
Seen this way, then, QTLs are necessary as they are, in effect, the critical KRIs. QTLs are focused on detecting
critical trial-level risks. Because they are focused on the critical, it is expected there would be only a small number
in a trial (typically up to five). KRIs monitor risks at all levels and there are typically many of these (See Q18).
Interestingly, ICH E6 R3 (draft) replaces QTLs with the term " acceptable ranges " :
The sponsor should set acceptable ranges to support this process within which variation can be accepted.
Where deviation beyond these ranges is detected, an evaluation should be performed to determine if there
is a possible systemic issue and if action is needed.
If this wording remains in the adopted ICH E6 R3, the debate is likely to continue - trying to understand and
agree the differences and similarities between KRIs, QTLs and " acceptable ranges " .
In summary then, QTLs can be seen as a subset of critical trial-level KRIs. Both QTLs and KRIs add value. But
QTLs are the only ones required by international guidance. Watch this space, though, because this is a continually
evolving area.
19.20 Q. Are there ways to get an early signal of whether a QTL is likely to be deviated from?
A. Q18 and Q19 have focused on the purpose and use of KRIs and QTLs. As QTLs are focused on critical trial
risks, and also because they are required in the guidance ICH E6 (R2), there has been much industry discussion
on how to implement them, and how to get most value. TransCelerate Biopharma developed resources in this area
which are publicly available, and much used. They have defined a QTL Framework, compiled benchmarks and a
QTL Plan Template amongst other publications. The Framework includes the following on getting an early signal
from a QTL:
Setting early action thresholds are defined as a threshold lower than the QTL threshold (referred to
as " secondary thresholds " in the original TransCelerate QTL paper). Early action thresholds could
be specified for QTL parameters to provide trial teams with early opportunities to mitigate risks to
participant safety or reliability of trial results and avoid a QTL deviation. This added limit allows trial
teams to intervene before an important deviation from a QTL is observed, if desired.
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