# Presentation: 510650

## Risk of QT Interval Prolongation: Non-clinical and Clinical EvaluationDouglas C. Throckmorton, M.D.FDA 

## Outline

- Introduction
- Step 2 E14 Guidance
- Request for Comments, Future Directions

## Guidance

- Preliminary Concept Paper: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs

## This document provides guidance on the design, conduct and interpretation of clinical studies assessing the potential of non-antiarrhythmic drugs for delaying cardiac repolarization

- Goal of E14

## Background and Timeline of Project

- CPMP “Points to Consider Document” December 1997
- Health Canada “Draft Guidance Document” on clinical QT interval prolongation:  March 2001
- Combined Health Canada/ FDA “Proposed Concept Paper”:  November 2002
- Consultation Workshop, Washington D.C., January 2003
- ICH Meetings:  Tokyo, Brussels, Osaka, DC

## Progress in Washington

- Outcome:  regional agreement on language for Step 2 document

## Future Directions

- Release of document for public comment
- items for specific comment identified in document
- general comment
- Ongoing FDA review of internal data, pre-clinical and clinical
- Step 4 Brussels May 2005 (pending comments)

## Selected Issues

- Use of pre-clinical data
- Thresholds for regulatory and clinical concern
- Definition of negative ‘thorough QT/QT study’

## When (and How) to Assess QT?

- ‘At present, whether non-clinical testing can exclude a clinical risk for QT/QTc prolongation is controversial.  Conduct of the ‘thorough QT/QTc study’, as described in section 2.1.2, would be needed in almost all cases for regions where non-clinical data are not considered able to preclude risk of QT/QTc prolongation.  For regions where non-clinical data are considered informative enough about the risk of QT/QTc prolongation in humans, the recommendations in this guidance for the clinical evaluation of QT/QTc could be modified.’

## Thresholds for Concern

- ‘It is difficult to determine whether there is an effect on the mean QT/QTc interval that is so small as to be of no consequence.  However, drugs that prolong the mean QT/QTc interval by around 5 ms or less do not appear to cause TdP.  On that basis, the positive control (whether pharmacological or non-pharmacological) should be well-characterized and consistently produce an effect corresponding to the largest change in the QT/QTc interval that is currently viewed as clinically not important to detect (a mean change of around 5 ms or less).’

## ‘Negative’ Thorough QT/QTc Study

- ... a negative ‘thorough QT/QTc study’ is one where the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTc interval is around 5 ms or less, with a one-sided 95% confidence interval that excludes an effect >8.0 ms.  This upper bound was chosen to reflect the uncertainty related to the variability of repeated measurements.  As with other data, the presence of outliers (see section 3.2.2) should also be explored.

## Consequences of ‘Thorough’ Study

## Phase 2 and 3 Evaluation

- Need for QT assessment depends on findings from ‘thorough’ study:
- No evidence of QT effect
- ‘The collection of baseline and periodic on-therapy ECGs in accordance with the current investigational practices in each therapeutic field is, in general, considered appropriate.’
- Collection of ECGs following adverse events (surprises happen!)

## Phase 2 and 3 Evaluation (cont)

- Evidence of QT effect
- Assessment of dose/concentration-response over time in target population
- Drug-drug and Drug-disease interactions
- Enhanced collection of  ECGs in pivotal studies
- Collection of extreme QT prolongation, symptoms

## Summary

- Step 2 Document to be publicly available soon (ICH website)
- Comments welcome

## WG Members

**D. C. Throckmorton**
**Rashmi Shah**
**Thierry Nebout**
**Borje Darpo**
**Keiji Ueda**
**Haruo Akagawa**
**Koji Todaka**
**Wataru Asakur**

**Maki Ito **
**Sadatomo Tasaka**
**Kihito Takahashi**
**Arata Kondo**
**Robert Temple**
**Philip T. Sager**
**Ronald J. Garutti**
**Hans Kemmler**
**Colette Strnad**