34th EMWA Conference
Clinical and Operational Challenges of
Paediatric Clinical Trials (Seminar)
Dr. med. Klaus Rose, M.D., M.S.
Pediatric Drug Development & More
klausrose Consulting
klaus.rose@klausrose.net
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Agenda
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Children are different from adults: physiology
Children are different from adults: ADME
Pediatric clinical trials
Existing & evolving structures for pediatric clinical trials
Relevant international guidelines
klaus.rose@klausrose.net
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Agenda
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Children are different from adults: physiology
Children are different from adults: ADME
Pediatric clinical trials
Existing & evolving structures for pediatric clinical trials
Relevant international guidelines
klaus.rose@klausrose.net
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Preterm Newborn: Phase of survival
born at < 36 weeks of gestation
Physiology:
Large body surface
Increased skin permeability
Reduced surfactant synthesis
Aortopulmonary shunts
Immaturity of the brain stem
No ciruclatory autoregulation
Incomplete retinal vascularisation
Very Preterm Newborn: Phase of survival
born at < 36 weeks of gestation
Pathophysiology:
Respiratory distress
Pulmonary hypertension
Patent ductus arteriosus
Apnea
Intraventricular hemorrhage
Retinopathy of prematurity (ROP)
Bronchopulmonary dysplasia
Term Newborn: Phase of Adaptation
age: birth up to 1 month
Physiology:
Large body surface
Increased skin permeability
Increased body water
Decreased blood brain barrier
Incomplete neuronal maturation
Increased hemolysis
Term Newborn: Phase of Adaptation
age: birth up to 1 month
Pathophysiology:
Sepsis
Hyperbilirubinemia
Seizures
Hypocalcemia
Hypoglycemia
Malformations
Infants and Toddler:
Phase of proliferation and growth
age: 22 days to 24 months
Physiology:
Small airways
Ongoing cerebral myelination
Naive (incompetent) immune system
Large liver and kidney (increased clearances)
Infants and Toddler:
Phase of proliferation and growth
age: 22 days to 24 months
Pathophysiology:
Otitis media
Bronchiolitis
Febrile seizures
Rickets
Children:
Phase of Differentiation and Training
age: 2 to 11 years
Physiology:
Slower growth rate
Increased independence
Increased school performance
Shift to logical operations
Children:
Phase of Differentiation and Training
age: 2 to 11 years
Pathophysiology:
Accidence
Dysfunctions of the immune system:
Asthma/allergy
Juvenile rheumatoid arthritis
Autoimmune diseases
Neoplasm
Hyperkinesia
Enuresis
Organ transplantations
Epileptic syndromes
Obesity
Diabetes
Adolescents: Sexual Maturation
age: 12 to 17 years
Physiology:
Rapid body changes:
growth spurt
gonadal growth
Emotional instability
Adolescents: Sexual Maturation
age: 12 to 17 years
Pathophysiology:
Acne vulgaris
Endocrine dysfunctions
Accidence
Sexual transmitted diseases
Drug addiction
Doping
Pre-term Infant
Term Newborn
Infant
< 36 weeks of gestation
Infant/Toddler
Child
Adolescent
28 days -23 months
2 - 11 years
12 - 17 years
Growth
Training
Maturation
0-27 days
Adaptation
Survival
Seyberth, in Pädiatrie, eds Speer/Gahr, 2005
Age Groups as per ICH E 11
Preterm newborn infants
(0 - 27 days)
Term newborn infants
(0 - 27 days)
Infants and toddlers
(28 days to 23 months)
Children (2 - 11 years)
Adolescents 12-16/17 y
- 18 18
Agenda
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Children are different from adults: physiology
Children are different from adults: ADMET
Pediatric clinical trials
Existing & evolving structures for pediatric clinical trials
Relevant international guidelines
klaus.rose@klausrose.net
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Key Publication
Kearns, 2003,
NEJM
• Absorption,
Distribution,
Metabolization,
Excretion in children
are different from
adults
• Maturation with age is
not linear and not in
parallel
• Variability much
higher
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ADME In Children
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Kearns et al, NEJM
2003
Drug Absorption
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Gastric emptying delayed in infants < 6 mo of age
Gastric acid production reaches adult levels by age 3 y
Gastric mucosa less developed than adults
In adults, gastric emptying biphasic
Preterm infant emptying slow and linear
Small infants require 6-8 hrs
Gastrointestinal absorption comparable to adults by 3
months
Distribution: Protein binding lower in newborns
• Lower albumin and a1-acid glycoprotein
• Decreased affinity of fetal albumin
• Endogenous competitors (e.g., bilirubin)
• Local anesthetics are less protein bound
• May increase free fraction - increased risk for
toxicity
Distribution: Increased Total Body Water
• Newborn: 70% body wt vs.. 55% in adult
• Larger ECF (40% v. 20% in adults)
• Larger volumes of distribution (Vd)
• Lower peak blood level (but same at steady state)
Neonatal Analgesic Clearance Delayed
• Immature hepatic enzymes
• Decreased during first weeks of life:
– Renal blood flow
– Glomerular filtration
– Tubular secretion
Renal Clearance Compared to Adults:
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Neonates - decreased
Premature infants - decreased
Toddlers - increased
Children - increased
Renal Elimination
• Preterm infants generally need lower doses
(mg/kg) to maintain similar steady-state
concentrations
• Requires 6-12 months for renal function to
reach adult values
Pharmacokinetic Differences Term & Preterm Infants
Absorption:
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Gastric HCI-production
Bile flow
Bacterial intestinal growth
Enterohepatic circulation
Distribution:
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Body water
Body fat
Muscular mass
Plasma protein binding
Liver metabolism:
 Hydroxylation
 Glucoronidation
Renale excretion:
 GFR
 Tubular function
Dosage-principle in the NICU
• Given:
• Vd 
• Clearance 
• Result:
• Loading dose (LD) 
• Maintenance dose (MD) 
• Examples:
• Phenobarbital, Phenytoin,
Methylxanthine, Digoxin,
Aminoglykoside, Indometacin
Chloramphenicol, Furosemide
Toxicity Examples Early Infancy & Childhood
Target/ Organ
Drug
Effect
Teeth
tetracyclines
discoloration/ enamel
dysplasia
Genital tract
cyclophosphamide
infertility/ovarian failure
Immune system
tacrolimus
Lymphoproliferation,
diabetes
Heart
antracyclines
alkylating agents
methylphenidate
cardiotoxicity
heart failure
cardiovascular events e.g.
myocardial infarction
CNS
phenobarbital
glucocorticoides
methylphenidate
cisplatin
attention and memory
dysfunction
cerebral palsy
stroke
hearing loss
Kidney
furosemide
nephrocalcinosis
Bone
glucocorticoids
growth impairment
Agenda
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Children are different from adults: physiology
Children are different from adults: ADME
Pediatric clinical trials
Existing & evolving structures for pediatric clinical trials
Relevant international guidelines
klaus.rose@klausrose.net
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Types of Pediatric Studies
0.
1.
2.
3.
4.
Extrapolation / Modelling & Simulation
PK/PD: not in healthy children  phase I only in pediatric
patients!
Controlled clinical trials (Phase II – IV)
- Active control
- Placebo control
- No control (e.g. rare diseases)
Diagnostic studies
Non-interventional studies: long-term observation; registries;
epidemiological studies
Other categorisation: regulatory vs. Investigator initiated clin trials
FDA Pediatric Study Decision Tree
Reasonable to assume (pediatrics vs adults)
3 similar disease progression?
3 similar response to intervention?
YES TO BOTH
NO
Reasonable to assume similar
concentration-response (C-R)
in pediatrics and adults?
•Conduct PK studies
•Conduct safety/efficacy trials*
NO
NO
Is there a PD measurement**
that can be use to predict
efficacy?
YES
•Conduct PK studies to
achieve levels similar to adults
•Conduct safety trials
YES
•Conduct PK/PD studies to get
C-R for PD measurement
•Conduct PK studies to achieve
target concentrations based on C-R
•Conduct safety trials
klaus.rose@klausrose.net
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Patient Numbers
• As many patients as necessary, as few as possible
• Statistical significance and clinically relevant difference in the
chosen endpoint must be reached with the chosen case
numbers
• Rare adverse events will only be found in much larger case
numbers  often not possible in children!
• Design with repeated measurements in the same patient
might reduce number of needed patients
• Look for suitable surrogate endpoints, e.g. hospitalisation rate
or Δ in glomelar filtration rate for renal function
Parameters Requested in PIPs (Clinical Study Form)
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Type of study & study design
Type of control (placebo/ active control), justification,
Location (regions),
Test products; dose; route of administration,
Objective(s) of the study,
Number of patients (M/F) and per age group
Duration of treatment (incl post-study observation )
Main inclusion/exclusion criteria,
Endpoints (primary, secondary)
Sample size (more or less detailed as appropriate),
Power calculation: describe effect size expected,
Options in case of recruitment issues, interim analyses and
stopping rules,
• Statistical methods (Statistical methods to compare groups for
primary outcome & for additional analyses if relevant).
klaus.rose@klausrose.net
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Endpoint Examples
Drug
Indication
Surrogate Endpoint
ACEi, ARB, βblockers
Hypertension
BP lowering effect (DBP vs.
SBP)
Statins
Hyperlipidemia
LDL lowering effect
Atorvastatin
Atherosclerosis in children Carotid IMT
with lupus
Enalapril
Infant Single Ventricle
Growth
Mitral regurgitation post
AVSD repair
LV end-diastolic dimension
Z-score
Sildenafil
Pulmonary hypertension
Exercise tolerance
Ataluren
Duchenne’s muscular
dystrophy
6 min walk test
Operational Challenges Clinical Trials
• Recruitment & consent of parents
• Rule of the thumb: recruitment the easier the
more severe the disease
• > 90% of children with cancer participate in trials
• Parents’ associations can help recruiting
Operational Challenges Clinical Trials
• Patients dislike placebo control  recruitment ↓
• Facilities: if shabby, will hinder recruitment
• If there is no space for healthy brother to play,
mother will not return
• If study personnel is unfriendly, mother will not
return
• Monitor: should have pediatric experience
• Good monitoring as essential as good protocol
Blood Withdrawals
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Justify every drop in protocol/ to ethics committee
Define upfront maximum number of tries
Define priorities of exams if not enough blood
Offer anesthetic cream, but child/ parents decide!
Informed Consent & Assent
• Use different texts for different age groups
• From around 7 years on, child will understand
• Child’s signature is not legally binding, but should
be asked for as a token of respect
• Physician can override child’s dissent if there are
serious medical reasons
Ethics Committees / IRBs
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Have essential place between plan & execution
Should have sufficient pediatric experience
Not all of them know about EU pediatric legislation
Not all of them focus on ethical questions
Can be easy or difficult in the dialogue
Laboratory/ Central Laboratory
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Make sure they have normal values for all ages
Central Laboratory: negotiate with senior officer
Central lab should have pediatric experience
Define upfront priorities if not enough blood
Agenda
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Children are different from adults: physiology
Children are different from adults: ADME
Pediatric clinical trials
Existing & evolving structures for pediatric clinical trials
Relevant international guidelines
klaus.rose@klausrose.net
44
Structures for Pediatric Clinical Research
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EU network of networks: EnprEMA
Commercial CROs
Further academic research networks
National, European, US-American and International
disease-specific academic networks
• ESDP (European Society of Developmental Pharmacology)
• ICDRA (International Conference of Drug Regulatry
Authorities), coordinated by WHO
klaus.rose@klausrose.net
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European Network of Paediatric Research at
the European Medicines Agency (Enpr-EMA)
• Academic clinical networks, coordinated by EMA
• On EMA website: Enpr-EMA workshops;
• Three membership categories
1. Networks fulfilling all minimum criteria
2. Networks currently undergoing clarification
3. Networks currently not qualifying
• MCRN: medicines for children research network
klaus.rose@klausrose.net
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Category 1
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European Cystic Fibrosis Society Clinical Trials Network (ECFS-CTN)
European Network for Hyperkinetic Disorders (EUNETHYDIS)
European Paed Oncology Off-patent Medicines Consortium (EPOC)
Finnish Investigators Network for Pediatric Medicine (FINPEDMED)
German Neonatal Network (GNN)
Innovative Therapies for Children with Cancer (ITCC)
International BFM Study Group (I-BFM-SG)
Italian Paediatric Federation MCRN (FIMP - MCRN)
MCRN The Netherlands (MCRN NL)
Mother Infant Child Youth Research Network, Canada (MICYRN)
NIHR Medicines for Children Research Network (MCRN UK)
Newcastle CCLG Pharmacology Studies Group
Paediatric European Network for the Treatment of AIDS (PENTA)
Pediatric Rheumatology International Trials Organisation (PRINTO)
Scottish MCRN (Scotmcn)
United Kingdom Paediatric Vaccines Group (UKPVG)
European Group for Blood and Marrow Transplantation (EBMT)
Paediatric Network of Clinical Investigation Centers - CICPed
klaus.rose@klausrose.net
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Category 2
• Children Leukemia Group (CLG) (EORTC)
• Network of Excellence for Research in Paediatric
Clinical Care
klaus.rose@klausrose.net
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Category 3
Belgian Pediatric Drug Network – BPDN
EuroNeoNet
Eur Soc Paed Gastronenterology, Hepatol & Nutr (ESPGHAN)
Futurenest Clinical Research
International Pediatric Transplant Association (IPTA)
Irish Paediatric Clinical Research Network (IPCRN)
Juv Scleroerma Working Group - Paed Rheumatology Eur Soc
National Center Child Health and Development (NCCHD) Japan
Neocirculation
Paed European Network for the Treatment of Infection (PENTI)
Réseau d’Investigations Pédiatriques Produits de Santé (RIPPS)
Swedish Pediatric Society (BLF)
Paediatric Trial Network (AMIKI)
Italian Neonatal Network (INN)
klaus.rose@klausrose.net
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Levels Of External Support In Pediatric Drug Development
1 Strategic level: Reflect potential use in
children [same, similar, different from
adult use]. Advise on pediatric
epidemiology and mechanism of
disease in different age groups
Clinical specialists,
consultants,
2 Designing pediatric development plan
3
CROs, medical writers,
(general) & write PIP (EU)
regulatory/ pediatric
consultants, medical
writers
3. Design individual projects, e.g. clinical PedResearch Networks
studies, preclinical test batteries,
(EnprEMA); reg/ ped
technical formulation development etc consultants, CROs
4 Execute individual projects
PedResearch Networks
(EnprEMA), CROs
Agenda
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•
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Children are different from adults: physiology
Children are different from adults: ADME
Pediatric clinical trials
Existing & evolving structures for pediatric clinical trials
Relevant guidelines
klaus.rose@klausrose.net
51
Relevant Guidelines
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ICH E 11
Declaration of Helsinki (informed consent/ assent)
ICH E 6 (GCP)
ICH M 3 (Definition of safe contraception)
And about ten thousand more …
… and national guidelines & laws
klaus.rose@klausrose.net
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ICH E 11: Clinical Investigation of Medicinal
Products in the Pediatric Population*
• Binding agreement world wide between industry & authorities
• 2.4 Type of studies: “When a medicinal product is to be used …
for the same indication(s) as … in adults, the disease process is
similar…, and the outcome of therapy is likely to be comparable,
extrapolation from adult efficacy data may be appropriate.“
• And: “ … extrapolation of efficacy from older to younger
pediatric patients may be possible.”
• 2.4.2: “The principles in study design, statistical considerations &
choice of control groups … generally apply to pediatric efficacy
studies. There are, however, certain features unique to pediatric
studies … it may be necessary to develop, validate, and employ
different endpoints for specific age & developmental subgroups.”
*
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http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4/E11_Guideline.pdf
ICH M 3: Non-Clinical Safety Studies For Human
Clinical Trials For Pharmaceuticals
• Women of Child Bearing Potential (WCBP): concern for unintentional
exposure of an embryo/fetus; strong EU/ US / Japan differences in
timing of repro tox studies before inclusion of WCBP in clinical trials.
US require highly effective method of birth control as per ICH M 3
Note 3:
• “Highly effective methods of birth control are defined as those, alone
or in combination, that result in a low failure rate (i.e., less than 1%
per year) when used consistently and correctly. For subjects using a
hormonal contraceptive method, information regarding the product
under evaluation and its potential effect on the contraceptive should
be addressed.“
klaus.rose@klausrose.net
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The Declaration of Helskinki Version 2008
• Does not contain the words ‘child’ or ‘minor’
• Addresses vulnerable and incompetent research subjects
• Relevant §s: 9 & 28
klaus.rose@klausrose.net
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JUST ANNOUNCED !
Joint DIA/ EFGCP/ EMA Paediatric Forum 2012
The EU paediatric regulation in its 6th year:
From Learning to Adapting
26 & 27 September 2012
London, UK
Programme Committee:
Gesine Bejeuhr, VfA (Association of Researchbased Pharmaceutical Companies, Germany)
Irja Lutsar, PDCO member for Estonia
Cecile Ollivier, EMA, London, UK
Thorsten Olski, EMA, London, UK
Klaus Rose, klausrose Consulting, Switzerland
Thomas Severin, Novartis, Switzerland
Organised by :
In partnership with :
Conclusions
• Pediatric drug development has different meanings
• Academic lecturers focus on clinical pharmacology
and therapeutic outcomes
• Regulators focus on legal requirements
• Most companies struggle to meet legal requirements
• A few companies focus on medicines for children
• Some barriers against research with children have
fallen, others still need to be removed
klaus.rose@klausrose.net
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Thank You For
Your Attention!
klaus.rose@klausrose.net
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Back-Ups
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klaus.rose@klausrose.net
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Released May 2010
klaus.rose@klausrose.net
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