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Since the late 1990s, several blockbuster, noncardiac drugs including terfenadine (Seldane) (1,2), cisapride (Propulsid) (3,4), and grepafloxacin (Raxar) (5) have been associated with prolongation of the QT interval of the electrocardiogram (ECG), polymorphic ventricular tachycardia, torsades de pointes (TdP), and sudden cardiac death. Regulatory agencies such as the Food and Drug Administration (FDA) responded initially with severe labeling restrictions, but ultimately these drugs were withdrawn from the marketplace. Not surprisingly, sudden cardiac death owing to noncardiac drugs has become a major safety issue for the pharmaceutical industry and the agencies that regulate it. TdP is linked to defective repolarization and prolongation of the QT interval of the ECG. At the cellular level, the duration of the cardiac action potential duration (APD) is prolonged. The major membrane currents and channels that are involved are shown in Fig. 1 along with the action potential they generate (6). [ABSTRACT FROM AUTHOR]

Ever since it was introduced in routine clinical cardiology practice (1), the continuous ambulatory electrocardiogram (Holter ECG) has been routinely used for diagnostic assessment of patients with different types of heart disease like cardiac arrhythmias, transient ischemic episodes and silent myocardial ischemia. The incidence of cardiac arrhythmia and myocardial ischemia, as well as the assessment of heart rate variability on Holter ECG acquired continuously over 24 h or longer have been useful for predicting clinical disease outcomes (2-5). Likewise, Holter ECG is often used in clinical drug research for the monitoring of general cardiac safety of novel drugs under development, particularly during the early phase I trials. In contrast, Holter ECG has only rarely been used in drug development for the formal assessment of drug-induced effects on cardiac repolarization, and the experience of central ECG laboratories in measuring ECG intervals on Holter is limited. Pharmaceutical sponsors and patients alike would benefit if reliable QT/QTc assessment were possible by Holter ECG, whereby the continuous ambulatory digital 12-lead ECG would be used to substitute for standard resting supine 12-lead ECGs in the assessment of drug-induced QT/QTc prolongation. [ABSTRACT FROM AUTHOR]

Since 1996, worldwide regulatory authorities have been providing guidance on cardiac safety as assessed by the standard 12-lead electrocardiogram (ECG), with the European Union's Committee for Proprietary Medicinal Products (CPMP) document ("Points to Consider") for the evaluation of the potential for QT prolongation with noncardiovascular medicinal products in both preclinical and clinical studies. The initiative gained momentum with Health Canada's March 2001 draft guidance document entitled "Assessment of the QT Prolongation Potential of Non-Antiarrhythmic Drugs," and continued to evolve with the November 2002 joint FDA-Health Canada concept paper entitled, "The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs" (see http://www.fda.gov/cder/guidance/index.htm for details). Since 2002, an accelerating focus on cardiac safety in new drug development has been observed throughout the international clinical research industry. Throughout 2003 and 2004, cardiac safety guidance advanced from discussions held as part of the International Conference on Harmonization process, with strong input from research industry and regulatory authorities in Europe and Japan. [ABSTRACT FROM AUTHOR]

Recent regulatory guidances for electrocardiograph (ECG) analysis have caused new considerations and challenges for sponsors when designing new drug development programs. As part of these initiatives, the role of the ECG core laboratory has been redefined as a "trusted third party" for the generation, management, and delivery of digital ECG files. As a result, mandatory quality programs for the ECG core laboratory have expanded from assuring the accuracy and precision of key ECG endpoints to now including a complex combination of evolving technology, process, and data verification in the collection, evaluation, and management of digital data files. The successful collection of quality ECG data in the digital era is highly dependent upon superior technology and user training based on predefined processes to properly collect, identify, and process ECGs. [ABSTRACT FROM AUTHOR]

Cardiac safety of noncardiac drugs has become a major concern in recent years. Episodes of Torsade de Pointes (TdP) have been linked to QT prolongation from drugs such as the antihistamine terfenadine (1). Regulators have responded by routinely requesting QT prolongation studies in human subjects to determine a drug's effects on cardiac safety. The recent QT concept paper put forth by the US Food and Drug Administration (FDA) and Health Canada November 2002 discusses definitive QT studies with a positive control and being able to detect a change in QT on the order of 5 ms (2). [ABSTRACT FROM AUTHOR]

Prolongation of the QTc interval on the surface electrocardiogram (ECG) reflects a delay in ventricular repolarization, and, when drug-induced, it is almost always a result of inhibition of the rapid component of the delayed rectifier potassium current (IKr). The other current that is infrequently inhibited is its slow component (IKs). Drug-induced prolongation of the QTc interval, when excessive in the right setting, can be pro-arrhythmic and degenerate into torsade de pointes (TdP), a potentially fatal and unique form of polymorphic ventricular tachycardia. One review in 1993 concluded, "At present, our knowledge base about the relation of the QT interval and torsades de pointes is grossly incomplete" (1). Unfortunately, despite extensive research for more than a decade since, this still remains the case today. It is therefore not surprising that more than any other drug-induced adverse reaction, it has been responsible in recent times for the withdrawal of many drugs from the market. [ABSTRACT FROM AUTHOR]

The safety and regulatory needs to detect small drug-induced changes in the QT interval have created many challenges for the design and analysis of "thorough" QT studies. The measurement techniques available, the correlation between the RR interval and the QT interval, and the high variability in the QT interval have made the detection of changes in the QT interval difficult, and the verification of a lack of an effect on the QT interval even more difficult. The purpose of this chapter is to provide statistical and empirical rationales for key elements of study design, and statistical analysis that will control for sources of QT variability and will enhance study sensitivity. We will identify study design and statistical techniques to reduce QT variability, discuss the assumptions inherent in many of the choices available in study design, and recommend study designs based on these principles. [ABSTRACT FROM AUTHOR]

The safety and efficacy of a pharmaceutical product is evaluated during product development; however, safety surveillance must continue after marketing. One principal tool for postmarketing safety surveillance is the analysis of spontaneous (nontrial based) adverse reaction reports. Formal studies, either experimental or observational in design, are other means to further assess an approved product's safety. Although the term "phase IV studies" is used to describe studies conducted after a drug is marketed, this term does not reflect a particular study design. Epidemiologic cohort studies conducted in administrative databases are examples of study designs used to examine the safety of new products. Other powerful study designs, such as large and simplified clinical trials (SCTs), may also provide safety and effectiveness data to supplement pre-approval information. The purpose of this chapter is to describe limitations of the drug approval process and to discuss post-marketing methods useful for assessing cardiac arrhythmias, particularly as related to QTc interval prolongation. [ABSTRACT FROM AUTHOR]

Drugs in clinical development that potentially have effects on cardiac safety based on nonclinical data or findings in phase I, may require systematic cardiac safety assessments throughout phases II and III. Of major concern are drugs which cause the lethal, but rare, ventricular arrhythmia, torsades de pointes (TdP). Indeed, drugs intended for the general population that cause a one in one million incidence of TdP can be a significant public health concern (1,2). This risk cannot be adequately addressed in typical drug development programs by arrhythmia monitoring or adverse event reporting. However, drugs known to cause TdP are known to reproducibly perturb cardiac ventricular repolarization, an effect that is manifest on the standard 12-lead electrocardiogram (ECG) as prolongation of the QTc interval. Thus, QTc and the degree to which it is prolonged, is used as a surrogate marker for a drug's potential to cause TdP. This chapter will focus on the use of standard 12-lead ECGs in phases II and III clinical development to assess a drug's effect on cardiac intervals, durations, and morphologic patterns. [ABSTRACT FROM AUTHOR]

Drug-induced prolongation of the QTc interval, when excessive and in conjunction with the right risk factors, can degenerate into torsades de pointes (TdP), a frequently fatal form of polymorphic ventricular tachycardia. While it is clear that the QT interval on the electrocardiogram (ECG) may not be highly correlated with the risk of TdP, change in the QTc duration is the one relied upon by drug developers and regulatory authorities as the best predictor of a new drug's cardiac safety. As commented on by Dr. Robert Temple from the Food and Drug Administration (FDA) in an FDA co-sponsored public meeting in Shady Grove, MD, in January 2003, if a drug prolongs the QT interval this effect is the commonest cause of new drug development delays, disapprovals, or removal from the market. Such drugs have come from many different therapeutic groups and from many different, related, and unrelated chemical structures. Some examples include the antihistamine terfenadine; the antibiotic grepafloxacin; the antispasmodic terodiline; the calcium channel blocker lidoflazine; the atypical antipsychotic sertindole; the opioid levomethadyl; and the gastric prokinetic agent cisapride. [ABSTRACT FROM AUTHOR]

The interpretation of ECGs recorded during clinical drug trials shares many similarities with the clinical interpretation of ECGs, but also differs in several significant ways. The fundamental rules for measurement of ECG intervals and overall ECG interpretation (cardiac rhythm, conduction, etc.) are identical whether an ECG is recorded from a patient having chest pain in an emergency room, or from a healthy subject involved in a clinical drug trial. But, the overall purpose of the evaluation of two such ECGs differs greatly. [ABSTRACT FROM AUTHOR]

Many noncardiovascular drugs have the adverse effect to delay cardiac repolarization, a phenomenon that can be quantified in humans on the surface electrocardiogram (ECG) by the QT interval (1,2). Despite a number of limitations associated with its assessment, the drug-induced prolongation of QT interval is considered an important marker for the risk of life-threatening arrhythmias (torsades de pointes [TdP]) (3,4). [ABSTRACT FROM AUTHOR]