Current challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative

doi:10.1016/j.ahj.2009.06.007

American Heart Journal

Volume 158, Issue 3, September 2009, Pages 317-326

https://doi.org/10.1016/j.ahj.2009.06.007 Get rights and content

In October 2008, in a public forum organized by the Cardiac Safety Research Consortium and the Health and Environmental Sciences Institute, leaders from government, the pharmaceutical industry, and academia convened in Bethesda, MD, to discuss current challenges in evaluation of short- and long-term cardiovascular safety during drug development. The current paradigm for premarket evaluation of cardiac safety begins with preclinical animal modeling and progresses to clinical biomarker or biosignature assays. Preclinical evaluations have clear limitations but provide an important opportunity to identify safety hazards before administration of potential new drugs to human subjects. Discussants highlighted the need to identify, develop, and validate serum and electrocardiogram biomarkers indicative of early drug-induced myocardial toxicity and proarrhythmia. Specifically, experts identified a need to build consensus regarding the use and interpretation of troponin assays in preclinical evaluation of myocardial toxicity. With respect to proarrhythmia, the panel emphasized a need for better qualitative and quantitative biomarkers for arrhythmogenicity, including more streamlined human thorough QT study designs and a universal definition of the end of the T wave. Toward many of these ends, large shared data repositories and a more seamless integration of preclinical and clinical testing could facilitate the development of novel approaches to both cardiac safety biosignatures. In addition, more thorough and efficient early clinical studies could enable better estimates of cardiovascular risk and better inform phase II and phase III trial design. Participants also emphasized the importance of establishing formal guidelines for data standards and transparency in postmarketing surveillance. Priority pursuit of these consensus-based directions should facilitate both safer drugs and accelerated access to new drugs, as concomitant public health benefits.

Section snippets

Cardiotoxicity, troponin, and other biomarkers: where do they fit in drug development?

Drug-induced cardiac injury can be evaluated in a number of ways, including ex vivo pathologic examination, in vivo cardiac imaging, and serum biomarker evaluation. Across the spectrum of preclinical and clinical cardiac safety testing, highly specific serum markers have gained attention and interest for their potential to provide sensitive “early warning” of myocellular injury and death. There are many biomarkers of cardiotoxicity in various stages of maturity including natriuretic peptides

Preclinical and clinical testing for QT proarrhythmia: How do they relate to one another and to risk of life-threatening arrhythmic events?

Long QT-mediated polymorphic ventricular tachycardia, or torsade de pointes, is a sudden and potentially lethal arrhythmia that has drawn attention as a cause for early termination of drug development and postapproval pharmaceutical withdrawal.¹⁷ Cisapride and terfenadine are two notable examples of drugs which were found to cause torsade de pointes after they were approved and in wide clinical use.18, 19 Unfortunately, the relationship between surrogate measures of action potential and QT

Preclinical QT-proarrhythmia testing

The International Conference on Harmonization (ICH) S7B guidelines²¹ require preclinical studies to assess the risk of QT prolongation. The risk of QT prolongation is often assessed through in vitro Human ether-a-go-go-related gene product (hERG) testing. The hERG channel is responsible for the rapid component of the delayed rectifier potassium current (I_Kr) and is almost always the cause for drug-related acquired long QT syndrome. Unfortunately, testing for I_Kr inhibition is not sufficient. In

The thorough QT/QTc study

The ICH E14 Guideline codifies and establishes methodology for the thorough QT/QTc study (TQT). E14 recommends that all drugs should be evaluated with a TQT.²⁵ The goal of the TQT is to detect the degree of QT prolongation attributable to peak serum concentrations of either the active drug or its metabolites. To this end, healthy volunteers are given significant doses of investigational drug and the QT interval is measured using high-fidelity digital electrocardiograph (ECG) recordings (Figure 1

Preclinical and clinical evaluation of non-QT proarrhythmia

QT prolongation is not the only mechanism by which drugs can cause proarrhythmia. Several notable examples of non–QT-mediated proarrhythmia include ventricular tachycardia precipitated by Vaughan-Williams class Ic agents (eg, flecainide toxicity), methylxanthine-induced atrial fibrillation, sinus node dysfunction after β-blocker therapy, and the multiple triggered arrhythmias which can be seen in the setting of digitalis toxicity.5, 31, 32 The mechanisms surrounding non-QT proarrhythmia are

Biologics and large molecules: how to evaluate proarrhythmia and myotoxicity when a thorough QT study cannot be performed

Because of the size of most biologics, such as antibodies or other large molecule therapeutics (usually >140,000 d), cardiotoxicity resulting from direct hERG channel blockade is generally not a concern.²³ As a result, their off-target electrophysiologic liabilities are limited and there is low risk for QT-mediated proarrhythmia. Known exceptions include scorpion toxin, which can bind the outer pore of the hERG channel, and oxytocin, which has been reported to prolong the QTc.36, 37 Although

Do we need “thorough” blood pressure, heart rate, platelet, and lipid studies?

Preclinical safety evaluations are heavily influenced by the ICH S7B guidelines.²¹ Despite the fact that most preclinical evaluations go beyond the S7B guidelines, some aspects of preclinical cardiovascular risk assessment could be improved to provide a more inclusive evaluation of overall cardiac function.

Preclinical cardiovascular safety assessment generally includes a defined cardiovascular safety study performed before the onset of clinical testing. These studies include an evaluation of

Risks and benefits of developing drugs with safety signals

The Critical Path Initiative highlighted the decline of new drugs entering clinical practice in the face of escalating costs and enormous commitment of resources by the pharmaceutical industry.¹² In light of this investment-return mismatch, some attention has been focused on whether or not the development of some new drugs may have been terminated prematurely owing to preclinical safety signals before they had a chance to be fully evaluated for clinical relevance. Unfortunately, there is a

Future directions

The current paradigm for evaluating clinical safety begins with preclinical animal modeling and progresses to clinical biomarker assays. “Thorough” studies of high-leverage surrogate markers for important clinical outcomes (such as blood pressure) and targeted, specific clinical biomarkers with a proven correlation with end-organ toxicity are needed. Just as the relationship between structure and receptor affinity is important in medicinal chemistry, the relationship between preclinical

Consensus goals

1.
Identify, develop, and validate specific clinical biomarkers indicative of early drug-induced myocardial toxicity.
2.
Build consensus regarding the use and interpretation of troponin assays in preclinical evaluation of myocardial toxicity.
3.
Encourage and promote preclinical data repositories to enable data sharing and foster collaborative interpretation and analysis of relevant end points for cardiac safety assessment.
4.
Identify better qualitative and quantitative biomarkers for arrhythmogenicity.
5.

Disclosures

Dr. Piccini is supported by an American College of Cardiology Foundation/Merck Award and has research funding from Boston Scientific. Dr. Whellan holds a contract with Duke University as a provider of electrocardiographic corelab services. Drs. Berridge and Finkle are employed by GlaxoSmithKline. Dr. Stockbride and Syril Pettit report that they have no disclosures. Dr. Vargas is employed by Amgen, Inc. Dr. Valentin is employed by AstraZeneca. Dr. Krucoff holds grants and provides moderate

References (50)

O'BrienP.J.
Cardiac troponin is the most effective translational safety biomarker for myocardial injury in cardiotoxicity
Toxicology
(2008)
VargasH.M. et al.
Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics
J Pharmacol Toxicol Methods
(2008)
ShahR.R. et al.
Refining detection of drug-induced proarrhythmia: QT interval and TRIaD
Heart Rhythm
(2005)
KligfieldP. et al.
Relation of QT interval measurements to evolving automated algorithms from different manufacturers of electrocardiographs
Am J Cardiol
(2006)
PicciniJ. et al.
Cases from the Osler Medical Service at Johns Hopkins University
Am J Med
(2003)
LehtonenA. et al.
Further evidence of inherited long QT syndrome gene mutations in antiarrhythmic drug-associated torsades de pointes
Heart Rhythm
(2007)
HillA.P. et al.
Mechanism of block of the hERG K⁺ channel by the scorpion toxin CnErg1
Biophys. J.
(2007)
GrazetteL.P. et al.
Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy
J Am Coll Cardiol
(2004)
WeberM.A.
Safety issues during antihypertensive treatment with angiotensin converting enzyme inhibitors
Am J Med
(1988)
FungM. et al.
Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceuticals markets — 1960 to 1999
Drug Inf J
(2001)

StephensM.

Introduction

Astemizole: voluntary withdrawal: Janssen, USA

(1999)

HenneyJ.E.

Withdrawal of troglitazone and cisapride

JAMA

(2000)

The Cardiac Arrhythmia Suppression Trial (CAST) Investigators

Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction

N Engl J Med

(1989)

PackerM. et al.

Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE trial

Circulation

(1993)

OwensÂ.J. et al.

Antimicrobial safety: focus on fluoroquinolones

Clin Infect Dis

(2005)

GarberA.M.

An uncertain future for cardiovascular drug development?

N Engl J Med

(2009)

SunS.X. et al.

Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization

Curr Med Res Opin

(2007)

FDA announces plan to halt marketing of terfenadine

Am J Health Syst Pharm

(1997)

ShahR.

Withdrawal of terodiline: a tale of two toxicities

PittsP.J.

FDA and the critical path to twenty-first-century medicine

J Med Philos

(2008)

O'BrienP.J. et al.

Cardiac troponin T is a sensitive, specific biomarker of cardiac injury in laboratory animals

Lab Anim Sci

(1997)

AppleF.S. et al.

Analytical characteristics of commercial cardiac troponin I and T immunoassays in serum from rats, dogs, and monkeys with induced acute myocardial injury

Clin Chem

(2008)

JaffeA.

Elevations in cardiac troponin measurements: false false-positives

Cardiovasc Toxicol

(2001)

RodenD.M.

Drug-induced prolongation of the QT interval

N Engl J Med

(2004)

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Progress in CardiologyCardiac Safety Research Consortium ConferenceCurrent challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative

Section snippets

Cardiotoxicity, troponin, and other biomarkers: where do they fit in drug development?

Preclinical and clinical testing for QT proarrhythmia: How do they relate to one another and to risk of life-threatening arrhythmic events?

Preclinical QT-proarrhythmia testing

The thorough QT/QTc study

Preclinical and clinical evaluation of non-QT proarrhythmia

Biologics and large molecules: how to evaluate proarrhythmia and myotoxicity when a thorough QT study cannot be performed

Do we need “thorough” blood pressure, heart rate, platelet, and lipid studies?

Risks and benefits of developing drugs with safety signals

Future directions

Consensus goals

Disclosures

Toxicology

J Pharmacol Toxicol Methods

Heart Rhythm

Am J Cardiol

Am J Med

Heart Rhythm

Biophys. J.

J Am Coll Cardiol

Am J Med

Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceuticals markets — 1960 to 1999

Drug Inf J

Introduction

Astemizole: voluntary withdrawal: Janssen, USA

Withdrawal of troglitazone and cisapride

JAMA

Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction

N Engl J Med

Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE trial

Circulation

Antimicrobial safety: focus on fluoroquinolones

Clin Infect Dis

An uncertain future for cardiovascular drug development?

N Engl J Med

Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization

Curr Med Res Opin

FDA announces plan to halt marketing of terfenadine

Am J Health Syst Pharm

Withdrawal of terodiline: a tale of two toxicities

FDA and the critical path to twenty-first-century medicine

J Med Philos

Cardiac troponin T is a sensitive, specific biomarker of cardiac injury in laboratory animals

Lab Anim Sci

Analytical characteristics of commercial cardiac troponin I and T immunoassays in serum from rats, dogs, and monkeys with induced acute myocardial injury

Clin Chem

Elevations in cardiac troponin measurements: false false-positives

Cardiovasc Toxicol

Drug-induced prolongation of the QT interval

N Engl J Med

Progress in Cardiology
Cardiac Safety Research Consortium Conference
Current challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative