This document discusses drug development for pediatric acute heart failure. There are several challenges including heterogeneous patient populations ranging from infants to older children with different conditions like cardiomyopathy or congenital heart disease. Currently approved drugs for acute heart failure in Europe include dobutamine, milrinone, epinephrine, and digoxin, but they were approved based on studies in adults and mechanisms of heart failure differ between pediatric and adult patients. Low cardiac output syndrome is a major issue following surgery for congenital heart defects, affecting 25-65% of patients, and studies have found milrinone may decrease the risk of low output. However, more research is needed due to diverse causes and presentations of pediatric acute heart failure.

1. Drug Development in
Pediatric Acute Heart Failure
Drug Development in
Pediatric Acute Heart Failure
Fraz Ahmed Ismat, MDFraz Ahmed Ismat, MD

2. 2
Success of Surgical Treatment of CHD
Raissadati JACC 2016

3. 3
Failure of Demonstrating Benefits of
Pediatric Heart Failure Treatments
Shaddy AJC 2017

4. Treatment Pathway for Pediatric Heart Failure
I II III IV Intractable
Symptoms
Patients
ACE Inhibitor
Aldosterone Antagonist
Intravenous Inotropy
Mechanical Support
NYHA / Ross Symptom Class
Hospitalization
Intermittent Diuretics
β-blocker
4
Kantor
Can J Card
2013

5. Particular Challenges of Pediatric
Heart Failure Development
No consensus
on optimal
study
designs
Absence of well-
defined & validated
clinical endpoints
CHMP AHF Guideline
Paediatric Addendum
(EMA/CHMP/107532-2013)
Low patient
numbers
Heterogeneous
populations
5

6. 6
PANORAMA-HF Study
Shaddy AHJ 2017

7. PANORAMA-HF Study
7
Shaddy AHJ 2017

8. 8
Shaddy AHJ 2017

9. Treatment Pathway for Pediatric Heart Failure
I II III IV Intractable
Symptoms
Patients
ACE Inhibitor
Aldosterone Antagonist
Intravenous Inotropy
Mechanical Support
NYHA / Ross Symptom Class
Hospitalization
Intermittent Diuretics
β-blocker
9
Kantor
Can J Card
2013

10. …Concentrating on Acute Heart Failure
I II III IV Intractable
Symptoms
Patients
ACE Inhibitor
Aldosterone Antagonist
Intravenous Inotropy
Mechanical Support
NYHA / Ross Symptom Class
Hospitalization
Intermittent Diuretics
β-blocker
10
Kantor
Can J Card
2013

11. Approved Drug Indication and Age Group
Dobutamine 5 mg/mL,
solution for infusion
Paediatric Indication(s)
Dobutamine is indicated in all paediatric age groups (from neonates to 18 years of age) as
inotropic support in low cardiac output hypoperfusion states resulting from decompensated
heart failure, following cardiac surgery, cardiomyopathies, and in cardiogenic or septic shock.
Milrinone 1 mg/mL
concentrate for
solution for infusion
Paediatric Indication(s)
Milrinone is indicated for the short-term treatment (up to 35 hours) of severe congestive heart
failure unresponsive to conventional maintenance therapy (glycosides, diuretics, vasodilators,
and/or angiotension converting enzyme [ACE] inhibitors); acute heart failure, including low
output states following cardiac surgery.
Adrenaline
(epinephrine) 1:10,000
Sterile Solution Minijet
Adult and Paediatric Indication(s)
Adjunctive use in the management of cardiac arrest. In cardiopulmonary resuscitation.
Intracardiac puncture and intramyocardial injection of adrenaline may be effective when
external cardiac compression and attempts to restore the circulation by electrical defibrillation
or use of a pacemaker fail.
Digoxin 250 µg/mL
Solution for Injection
Adult and Paediatric Indication(s)
Digoxin is indicated in the management of chronic cardiac failure where the dominant problem
is systolic dysfunction. The therapeutic benefit of digoxin is greater in patients with ventricular
dilatation. Digoxin is specifically indicated where cardiac failure is accompanied by atrial
fibrillation.
Approved Drugs for Pediatric Acute Heart Failure (EU)
11

12. 12
Kreutzer
JTCVS 1973
The “Fontan” Operation

13. 13
Hsu Curr Opin Peds 2015

14. 2 y/oBirth 18 y/o
Age Distribution of Pediatric Acute Heart Failure (AHF)
14
Age
Frequency
Fontan

15. The Population of Pediatric Acute Heart Failure (AHF)
Long-standing heart failure (HF) with acute decompensation
• Relatively rare
• Predominantly older children
• Definitive treatment with transplantation
• Cardiomyopathy (CM)
• Palliated congenial heart disease (CHD); e.g. Fontan
Morbidity: mechanical support or transplant; mortality seen with long hospitalizations
Pediatric
AHF
Cardiomyopathy
Palliated CHD
(Fontan)
Long-standing
HF with acute
decompensation
predominantly older children
15

16. 2 y/oBirth 18 y/o
Age Distribution of Pediatric Acute Heart Failure (AHF)
16
Age
Frequency
Fontan
Cardio-
myopathies

17. The Diversity of Pediatric Cardiomyopathies
Lee
Circ Res
2017 17

18. The Population of Pediatric Acute Heart Failure (AHF)
Pre-OP Congenital Heart Disease (CHD)
Long-standing heart failure (HF) with
acute decompensation
• Relatively numerous
• Predominantly younger children
• Relatively rare
• Predominantly older children
• Definitive treatment with transplantation
• Treated with definitive surgical or catheter-based
intervention
• Palliative medical support (e.g. PGE2)
• Cardiomyopathy (CM)
• Palliated congenial heart disease (CHD);
e.g. Fontan
Morbidity: mechanical circulatory support,
increased length of stay; mortality rarely observed
Morbidity: mechanical support or transplant;
mortality seen with long hospitalizations
Pediatric
AHF
Pre-OP CHD
Cardiomyopathy
Palliated CHD
(Fontan)
Long-standing
HF with acute
decompensation
predominantly
younger children
predominantly older children
18

19. 2 y/oBirth 18 y/o
Age Distribution of Pediatric Acute Heart Failure (AHF)
19
Age
Frequency
Unrepaired
CHD
Fontan
Cardio-
myopathies

20. 20
Parr
Circ 1975

21. Parr
Circ 1975
Low Cardiac Output Predicts Death
after CHD Repair
21

22. Low Cardiac Output following CHD Surgery 20 Years Later
Wernovsky
Circ 1995
22

23. 23

24. 24
2016
2016
25-65%
25-65%

25. The Population of Pediatric Acute Heart Failure (AHF)
Low Cardiac Output Syndrome (LCOS) in
Post-OP Congenital Heart Disease (CHD)
Long-standing heart failure (HF) with
acute decompensation
• Relatively numerous
• Predominantly younger children
• Relatively rare
• Predominantly older children
• Definitive treatment with transplantation
• ~25% of congenital heart disease (CHD) surgery
• Cardiopulmonary bypass (CPB) main risk factor
• Cardiomyopathy (CM)
• Palliated congenial heart disease (CHD);
e.g. Fontan
Morbidity: mechanical circulatory support,
increased length of stay; mortality rarely observed
Morbidity: mechanical support or transplant;
mortality seen with long hospitalizations
Pediatric
AHF
Pre-OP CHD
Not a therapeutic target
Post-OP CHD
(LCOS)
Cardiomyopathy
Palliated CHD
(Fontan)
Long-standing
HF with acute
decompensation
predominantly
younger children
predominantly older children
25

26. 2 y/oBirth 18 y/o
Age Distribution of Pediatric Acute Heart Failure (AHF)
26
Age
Frequency
LCOS
Unrepaired
CHD
Fontan
Cardio-
myopathies

27. Approved Drug Indication and Age Group
Dobutamine 5 mg/mL,
solution for infusion
Paediatric Indication(s)
Dobutamine is indicated in all paediatric age groups (from neonates to 18 years of age) as
inotropic support in low cardiac output hypoperfusion states resulting from decompensated
heart failure, following cardiac surgery, cardiomyopathies, and in cardiogenic or septic shock.
Milrinone 1 mg/mL
concentrate for
solution for infusion
Paediatric Indication(s)
Milrinone is indicated for the short-term treatment (up to 35 hours) of severe congestive heart
failure unresponsive to conventional maintenance therapy (glycosides, diuretics, vasodilators,
and/or angiotension converting enzyme [ACE] inhibitors); acute heart failure, including low
output states following cardiac surgery.
Adrenaline
(epinephrine) 1:10,000
Sterile Solution Minijet
Adult and Paediatric Indication(s)
Adjunctive use in the management of cardiac arrest. In cardiopulmonary resuscitation.
Intracardiac puncture and intramyocardial injection of adrenaline may be effective when
external cardiac compression and attempts to restore the circulation by electrical defibrillation
or use of a pacemaker fail.
Digoxin 250 µg/mL
Solution for Injection
Adult and Paediatric Indication(s)
Digoxin is indicated in the management of chronic cardiac failure where the dominant problem
is systolic dysfunction. The therapeutic benefit of digoxin is greater in patients with ventricular
dilatation. Digoxin is specifically indicated where cardiac failure is accompanied by atrial
fibrillation.
Approved Drugs for Pediatric Acute Heart Failure (EU)
27

28. 28

29. Milrinone Associated with Decreased Clinical LCOS
Hoffman
Circ 2003
29

30. PRIMACORP Study Design
30
Hoffman
AHJ 2002
PK pharmacokinetics; R randomization; Sx surgery
Inclusion criteria:
eligible surgical procedures
Ventricular septal defect with interrupted
aortic arch
Arch hypoplasia
Coarctation of the aorta
Repair of transposition of the great arteries
by the arterial switch operation
Complete atrioventricular canal
Tetralogy of Fallot
Total anomalous pulmonary venous return
Truncus arteriosus
Double outlet right ventricle
(biventricular repair)
Anomalous left coronary from the
pulmonary artery
Congenital mitral valve anomaly
(may be reoperation)
Ross operation ± Konno procedure

31. Challenges in Pediatric AHF / LCOS Relative to
Traditional Pediatric Development
Traditional Pediatric Development Pediatric AHF / LCOS Development
Plausibility
Similarities in adult & pediatric
etiologies, physiology, treatment goals
Differences in adult & pediatric etiologies,
physiology, & treatment goals
Feasibility Similarities in presentation Heterogeneous paediatric populations
Ages
Older children > Younger Children >
Infants
Infants >> Older Children >> Younger Children
Adult
Older
Pediatric
Younger
Pediatric
Adult AHF
Older Pediatric
AHF
Younger
Pediatric
LCOS
Younger
Pediatric AHF
31

32. Backup
32

33. Pediatric Development Framework EU/US
EU – Paediatric Investigation Plan (PIP)
• Development plan aimed at ensuring that the necessary
data are obtained through studies in children
• Support the development and authorisation of a
medicinal product for all pediatric populations subset
• Agreed PIPs must be followed exactly → binding on
company upon MAA approval
• Modifications at later stage are possible
• PIPs must address a condition. There can be
different PIPs for different conditions.
• Within a certain condition, clear rationale & justification
for the indication(s) for which significant therapeutic
benefit is expected in paediatrics must be provided.
 PDCO can request “within that condition that the
indications may be expanded or decreased”.
• PIP is required if condition exists in children
regardless if adult indication exists in children
33
US – PREA/BPCA
Pediatric Research Equity Act (PREA)
• Triggered by an application for a new
drug/biologic, new indication, new dosage form,
new dosing regimen, new route of administration
or new active ingredient
• Required pediatric assessments of certain
approved drug/biologic indications
• PREA requirements are based on adult indication,
not condition
Best Pharmaceuticals for Children Act (BPCA)
• Provides for voluntary pediatric drug assessments
via a Written Request (WR), including clinical and
non-clinical studies for drugs and biologic agents
• Incentive is 6 months extension on patent, data,
orphan exclusivities (biologics no patent
extension)

34. EMA Pediatric AHF Guidelines EMA/CHMP/707532/2013
(adopted in Nov 2016; came into force on 1 June 2017)
Efficacy Evaluation – Suggested Endpoints (EPs)
Composites are acknowledged as advantageous in some cases (including ranked composites)
Clinical or Symptom Scores
• Could be useful as measures of efficacy provided their use
is validated and consistent
• NYHA, Ross or PHFI (defined a priori and justified)
Hemodynamic Measurements
• Should be linked to clinical outcomes
Biochemical Parameters (unlikely to be sufficient alone)
• Natiuretic peptides & inflammatory markers
• Could indicate severity and response to treatment
• Use is encouraged to establish link with clinical outcomes
Safety Evaluation
• Similar to adults with additional parameters important in
children (e.g. hypotension, hypoperfusion, arrhythmias,
renal functions etc.)
Mortality
• Recognized as rare event (all cause death or CV
death to be considered as composite EP)
“Time to” Events
• Transplantation, referral for transplantation
• Length of stay, LOS in ICU (can be influenced by
regional or organizational aspects)
• Time to worsening heart failure (useful in medium to
longer term studies)
Cardiac Function
• Echocardiographic measure of ventricular function
– End diastolic or systolic dimensions, end diastolic or
systolic volumes
– Ejection fraction, fractional shortening
• Anticipated to be linked to clinical measures of
outcomes
34