A quality tolerance limit is exceeded during a trial. What do you do?

Why

A quality tolerance limit is a trial level, pre-specified range for a measure tied to a critical to quality factor, such as the proportion of participants with a missing primary endpoint or the rate of important eligibility deviations. E6(R3) section 3.10.1.3 says that when a deviation beyond such a range is detected, an evaluation should determine whether there is a systemic issue and whether action is needed. Section 3.10.1.6 asks that important quality issues, including exceeded ranges, and the actions taken be reported in the clinical study report.

So the excursion is visible to regulators either way, and the question is whether the team can show it understood and handled it. Start by checking the data are right, since a slow data feed can make the rate look worse than it is. Then break the excursion down by site, country, time and process step.

A cluster at two sites suggests training. A spread across all sites suggests the protocol or a system is the cause, and might need an amendment.

How to work it through

1. Confirm the excursion is real by checking data completeness and the calculation.
2. Break the measure down by site, region, time period and process step to locate the cause.
3. Assess the impact on participant safety and on the primary analysis with the statistician.
4. Choose a proportionate action, such as retraining, a system fix or a protocol amendment.
5. Document the evaluation, decision and actions for the trial master file and the clinical study report.
6. Watch the measure afterward to confirm the action worked.

Where the answer stops holding

A limit is only useful if it was set from a sound rationale, such as historical data or the statistical design. A limit set too loosely will never trigger, and one set too tightly will trigger on noise. Exceeding a limit does not by itself mean the trial is compromised, and staying under it does not prove quality.