Make the QT case from Phase 1 data

What is at stake

A dedicated thorough QT study adds months and cost. When Phase 1 data are suitable, the ICH E14 Q&As (R3) allow concentration-QTc analysis to replace it. The 2022 E14/S7B Q&As describe how nonclinical data support the case when high exposures cannot be covered.

Question of interest

Can the QT assessment rely on concentration-QTc analysis of Phase 1 data instead of a dedicated thorough QT study?

A pre-specified linear mixed-effects concentration-QTc model, fitted to SAD/MAD ECG and PK data, estimates the QTc effect at therapeutic and high clinical exposures. It serves as the primary QT assessment, with nonclinical S7B data integrated where the E14/S7B Q&As apply.

What reviewers will ask

Do Phase 1 exposures cover the high clinical exposure scenario?

We check coverage at scoping against the expected DDI and organ-impairment exposures. If it falls short, you hear it before the analysis is commissioned.

Is there hysteresis, or a heart-rate effect?

Both are assessed before the model is fitted, and the model is adapted if the data call for it.

Was the analysis pre-specified?

The analysis plan is fixed before unblinding where possible, and every deviation is reported with its reason.

What you file with the agency

Concentration-QTc report and CSR section
QT summary for the briefing document
Request to replace the TQT study, with its supporting analyses
Analysis datasets and code

What we need from you

Time-matched ECG and PK data from SAD/MAD or another Phase 1 study, with placebo
The ECG core-lab specification and data transfer agreement
The expected therapeutic dose and known sources of high exposure (DDI, organ impairment)

Placebo-corrected change in QTcF against plasma concentration with a linear model fit and confidence band, below the 10 millisecond threshold at the supratherapeutic exposure. — Concentration-QTc relationship.

What it may replace

A thorough QT study, when Phase 1 exposure covers the high clinical exposure scenario and the analysis meets the ICH E14 Q&A criteria. The agency decides on the waiver.

Scientific approach

Data. Time-matched ECG and PK, heart-rate correction (QTcF, with a check of the correction), and an assessment of hysteresis before the model is fitted.

Model. The pre-specified linear mixed-effects model recommended in the scientific white paper underlying the E14 Q&As, with treatment-specific intercept and time effects, and checks of linearity and model fit.

Exposure coverage. Predictions at the high clinical exposure scenario. If Phase 1 exposure does not cover it by a sufficient margin, we say so: a waiver may not be supportable.

Sensitivity. Alternative correction methods, nonlinear models and exclusion analyses, reported alongside the primary result.

Relevant guidance: ICH E14 Q&As (R3), which allow C-QTc analysis to replace the TQT study; ICH E14/S7B Q&As (2022), on integrating nonclinical data; ICH M15.

Is this the decision in front of you?

Fixed price, paid in two milestones. A guaranteed date. Agency questions on this analysis answered at no extra cost. Pricing · How we work

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