# Presentation: 346389

## Evaluation of Cardiac Safety by ECG Findings: Focus on QTc Duration

- Joel Morganroth, M.D.
- Clinical Professor of Medicine
-  University of Pennsylvania
- Chief Scientist, eResearchTechnology

## Prolongation of the QTc Interval: Cardiac Safety Issue of New TherapyWhy?

- 	Increased risk of torsades de pointes (potentially fatal polymorphic ventricular tachycardia) as QTc interval increases - not all cases had QTc >500 msec

## Torsades de Pointes

## Drugs Discontinued from Marketing in Last Decade Due to QTc Effect

**Terodiline****	****	****GU**
**Terfenadine****	****	****Antihistamine****	**
**Astemizole****	****	****Antihistamine****	**
**Sertindole****	****	****CNS**
**Grepafloxacin****	****	****Antibiotic**
**Droperidol****	****	****CNS**
**Cisapride****	****	****GI**

## Terfenadine

- Mean change in QTc at clinical dose:
- 6 msec (retrospectively detected by digital manual ECG analysis after marketing)
- Mean change in QTc at Tmax (Mean max change) - 18 msec
- Max change in the presence of a metabolic inhibitor (ketoconazole) – 50-100 msec
- Benefit: 	reduce minimal symptoms
- Risk: 	death
- Result: 	Removed from the Market

## Other Drugs That Prolong the QTc Interval (some examples ONLY)

_**CNS**_: ziprasadone, thioridazine, risperidone
_**Antibiotics**_: clarithromycin, ketoconazole, fluconazole, moxifloxacin
_**Neoplastic Agents**_: arsenic, tamoxifen
_**Anti-rejection**_: tacrolimus
- Class I and III **Antiarrhythmic **Agents: 	quinidine, sotalol, amiodarone

## Drug-Induced Torsades

-  Primary: Drug effect (IKr block)
-  Secondary: Effect Modifiers
-  Bradycardia
-  Hypokalemia
-  Heart disease (LVH or CHF)
-  Atrial fibrillation
-  Female gender
-  Form Fruste HERG mutation
-  Metabolic inhibitors (pK); overdose
-  Concomitant IKr blockers (pD)

## What is the QT Interval?All other ECG Changes also Important

## KEY ECG Issues in New FDA-TDP Concept Paper November 2002

**All ECGs must be Recorded,Processed and Stored Digitally and using a central ECG laboratory -----****	****Paper ECGs, if needed, can be digitized **
**Analysis should be Manual (digipad or on screen) – ****	****Automated for “safety analysis” ? **
**An Intense or Thorough Phase I ECG Trial is required to rule out a 5 msec effect for all Bioactive Agents (important design features: negative and positive control and dose effect of new agent), and,**
**Digital Annotated ECG waveform raw data to be provided for critical ECG data using the XML.DTD**** **

## Sources of QTc Variability

- ECG Measurement Method + Correction formula of QT to QTc
- Frequency of ECGs Baseline and on Therapy ECGs (cover exposure, diurnal)
- Sample Size (need >30 per arm) for Power
- Population: volunteers with half females
- Dose Ranging (_>_ 3-5X prefer >10x) - ?need to study metabolic inhibitors
- Control Groups: negative and positive

## Corrected QT Interval - QTc

**QTc is the QT corrected for heart rate (QT decreases as the heart rate increases)**
**How to correct is the subject of FDA-TPD guidance: **
**Bazett formula (QT/RR****0.5****)**
**Undercorrects at low heart rates-most limitations**
**Fridericia formula (QT/RR****0.33****)**
**Least limitations of the fixed exponent correction**
**Population Based – find exponent for placebo treated and baseline QT and RR ECG data for a “disease”**
**Recommended for ISS ECG Analysis**
**Individual Based – find exponent for each subject using at least 50-100 ECGs at baseline (pre treatment)**
**Most accurate – best considered for definitive Phase I ECG Trial**

## Slide 12

## QTc Statistical Analysis

- 1. _**Central Tendency: Mean Change**_            	(Time point to time point requires several ECGs at each point)
- 2. _**Categorical analysis**__ __**looking for outliers**_:
- 	A. maximum Mean change
- 	*% change from baseline by:*
- 	B. 30-60 and > 60 msec change
- 	C. % who have a _new_ value > 500 msec
- 	D. % who have _new_ abnormal U waves
- 3. Don’t expect to see arrhythmias - symptoms

## Continuous Interval Analysis Regulatory Signals

-     **Mean Change* of QTc Duration**
- (Degree of outliers equally important)
-   < 5 msec    -	 probably no concern
- 5 - 10 msec  -  	 increasing concern
- 10-20 msec  - 	 uncertain concern
- > 20 msec    - 	 definite concern
_**BUT DEPENDS ON RISK-BENEFIT OF THERAPY**_

## Overall Cardiac Safety Determination of a New Agent

- Preclinical Data provides Clues but Trumped by Adequate Clinical Data
- Thorough Phase I ECG Trial Now 	Recommended to Judge Intensity of ECGs in Phase II and III
- Phase II and III ECG Data in the Target 	Population
- Integrated Summary of Cardiac Safety Should Provide Most Robust Analysis