TABLE 1. Modifications to Standard Drug Development Issues for QTc Interval Monitoring9,26-27.

ICH E14/standard concepts	Modifications in oncology
Healthy volunteers	Oncology patients, usually heavily pre-treated with other therapies; accept other risks of anti-cancer therapy; older population; total number of exposed patients < 1,000
Use of placebos, washout periods	Not appropriate
Use of positive controls	Only use drugs with benefit to cancer patients, such as anti-emetics
Supratherapeutic doses	No dosing higher than maximum tolerated or beneficial dose
Screen for cardiac disease, other medications	Many patients at high risk for cardiac disease; have other medical conditions
Normal QT interval values	Accept longer QTc interval at baseline and after dosing
Inpatient cardiac monitoring	Focus on drug concentration-QT interval association; average several ECG readings
Stop drug if QT interval prolonged	Dose reductions or drug holidays; re-consent with emphasis on greater TdP risk; risk minimization

RISK MINIMIZATION

Make very high risk patients ineligible

Change all other medications with potential cardiac toxicity

Exhaustive review of risk factors (age, gender, CHF, sudden death family)

Assess renal and hepatic function

Increase ECG, electrolyte monitoring with aggressive supplementation of electrolytes

Extensive, personal informed consent

Repeat informed consent with ECG changes

Set individual parameters for agent discontinuation

Patient not to accept other medications from physicians unaware of arrhythmic potential