Pediatric Therapeutics and Cardiovascular Safety

An Academic Clinical Overview

Victoria L. Vetter, M.D.Children’s Hospital of Philadelphia

University of PennsylvaniaSchool of Medicine

Pediatric Cardiovascular Disease Conditions

• Congenital heart defects• Congestive heart failure • Arrhythmias• Acquired heart disease• Systemic hypertension • Pulmonary hypertension

Major Cardiac Toxicities of Drugs in Children

• Developmental abnormalities– Structure and Function

• Decreased Cardiac Function• Arrhythmias

– Proarrhythmia– Conduction changes– Repolarization effects

• Long-term Cardiovascular Health– Increase coronary artery disease risks– Impair normal cardiac development

Cardiac Safety in Pediatrics

• Acute Safety – Triggering of cardiac events– Torsades de Pointes

• Short-term Safety– QTc prolongation– AV block, bradycardia

• Long-term Safety– Doxorubicin/anthracyclines– ↑HR or BP over time

Lipschultz S Semin Oncol 33:S8–S14; 2006

Why Does Cardiac Safety in Drugs and Devices Need Special Attention in Children?

Children Are Not Small Adults

Size and Other Differences between Children and Adults

• Doubling of body size by six months

• Triple body size by one year

• BSA doubles in first year

• Different presentation of diseases

What Makes Safety in Children Different from Adults?

• Developmental Vulnerability and Variability• Fetus• Neonate Adolescent• Puberty

• Exposure– Indirect maternal drugs

• Fetal• Breast feeding

• Dosing Variations– Pharmacodynamic and Pharmacokinetic Differences– Dosing by weight or BSA– Absence of dosing studies and “approved” labeling

What Makes Drugs Work Differently in Children?

• Developmental Changes– Absorption, Distribution, Elimination– Metabolism

• Hepatic Enzymes• Renal Clearance

• Extrapolation of drugs approved for adult use– Ineffective, Incorrect Administration– Toxicity

Impact of Unsafe Drugs in Children Thalidomide

•1961: FDA prevented approval, but several American children were born with the typical limb defects after exposure during “investigational” trials

•1962: Led to Amendments in the Food and Drug Act (Kefauver-Harris Amendment)

•Manufacturers had to prove efficacy and safety

How Can Cardiac Drug Safety in Children Be Improved?

• Regulation and Surveillance• Pediatric Labeling• Medication Error Prevention• Research

– To better understand safety risks– To develop safer, more effective drugs

Monitoring for Cardiac Safety• Effects on heart rate• Effects on blood pressure• Effects on ECG

– Heart rate– PR interval– QRS duration– QT/QTc intervals, QT dispersion, JT/JTc interval– ST-T wave changes

• Heart rate variability• Development of arrhythmias• Worsening of underlying arrhythmia• Biomarkers, e.g. troponin, BNP, others• Acute, short, mid and long-term effects• Post marketing changes in above along with AERs

Limitations of Pre-marketing Trials in Pediatrics

• Study population, age group • Limited number of pediatric trials • Few children are enrolled with minimal

data obtained• Limited prior knowledge of pediatric

efficacy, effectiveness and safety

Benefits of Post-marketing Studies in Children

• Pediatric information can be consolidated• Effectiveness of the drug for the original

indication in children• Other beneficial effects of the drug• Information on adverse effects in patients

different from study subjects (different ages)• Information on rare adverse effects not

previously seen in adults • Information on long-term safety

Why Is Pediatric Drug Research Not More Common?

• Smaller market for pharmaceuticals• Harder to enroll children in trials• Ethical issues of consent /assent

Problems• Children are denied useful drugs• Children are exposed to non-useful or

toxic drugs• Accurate dosing and efficacy not known

Cardiac Drug SafetyOngoing Problems with Pediatric Labeling

• Over 78% of drugs used in pediatrics don’t have labeling for use in pediatrics and/or for the indication for which they are used

Medical Errors in Drug Use in Pediatrics

• 31% error rate in pediatrics compared to 13% for adults (Crowley, Curr Ther Res 2001)

• 2.5% of medical errors in pediatrics result in harm (Kaushal JAMA 2001)

• 11 adverse drug events/100 pediatric admissions (Takata, Peds, 2008)

Common Sources of Medical Errors

• Calculation errors/Incorrect dose ordered– 70% of dosing errors

• Transcription errors/abbreviations• Lack of standard dosing for off-label use of

drugs• Lack of pediatric dosing formulations• Incorrect dose administered by caregiver

Challenges to Drug Safety in Children

• To develop better understanding of developmental variations

• Identify developmental windows of vulnerability• Identify pharmacogenomic and other differences that

increase or mitigate toxicities• Identify and understand molecular and cellular

mechanisms of drug toxicities• Collect information on overall adverse events and severe

adverse events such as death, either sudden or overall – A Sudden Cardiac Death Registry that provided drug

history and other information might help to identify signals from specific drugs

• Determine most effective monitoring methods for short and long-term drug effects

Device Safety and Development in Children

• Interventional Devices– Catheters (cutting, transseptal, balloon)– ASD, VSD, PDA occluder– Stents, coils– Transvenous pulmonary valve– Lead extraction devices– Electrophysiologic and mapping catheters

• Circulatory Support– Cardiopulmonary bypass/ECMO– Ventricular assist devices

• CIED (Cardiac Implantable Electrical Devices– Pacemakers, ICD, CRT, loop recorders

• Cardiac Surgery Devices (valves, conduits, etc)

• Interventional cardiology procedures reduce morbidity and mortality by avoidance of OHS in high risk patients

• Allows correction of anomalies that surgery can’t address

Unique Circumstances Interventional Devices in Children with CHD

• Multiple types of defects with variations in anatomy and with physiologic and pathophysiologic differences from adults

• Wide range of anatomic sizes amplified by somatic growth (3 fold increase); impact of growth differs by congenital defect

• Surgical procedures change venous access to the heart, result in residual lesions, postoperative sequellae

Unique Circumstances Interventional Devices in Children with CHD

• Small vascular and intracardiac structures limit access and increase risks

• Child is exposed to device for long time periods necessitating durability

• Devices will need to be replaced due to growth and/or deterioration over lifetime

• Children’s lifestyle much more active than adults, putting increased and different stresses on devices

Off-Label Device Use

• 473 patients• 595 interventions

– 63%/50% off-label device use

• Stents-99%• Balloon dilations-78%• Coils-29%

Beekman, et.al

Device Safety in Children

• Fractures• Device Size/Access• Recalls• Programming Adaptability• Lifelong Need

Device Safety and Development in ChildrenChallenges

• Design (small, variable sizes, unique needs)• Impact of growth, long-term device sequellae,

physiologic and pathophysiologic interactions with device

• Early identification of adverse events – Role of Registries

• Clinical Studies (numbers, time, ethics, costs)• Regulatory Issues

– Class III devices, IDE, PMA, HDE/HUD• Small Market

Device Safety and Development in Children

• Goal: To promote development of new effective and safe devices for the pediatric population in the current environment

Progress and Solutions• Novel Approval Pathways

• Registries• Extrapolation• Enhanced post market surveillance• Use of Outside US Data

• Legislation– 2007: Medical Device Improvement and Safety Act

Thank You