Clinical and Operational Challenges of Paediatric Clinical Trials (Seminar)

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Clinical and Operational Challenges of
Paediatric Clinical Trials (Seminar)
34th EMWA Conference

Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug
Development Moreklausrose Consultingklaus.rose
_at_klausrose.net
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• Agenda
• 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

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• Agenda
• 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

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Preterm Newborn Phase of survival born at lt 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
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Very Preterm Newborn Phase of survival born at lt
36 weeks of gestation
Pathophysiology Respiratory
distress Pulmonary hypertension Patent ductus
arteriosus Apnea Intraventricular
hemorrhage Retinopathy of prematurity
(ROP) Bronchopulmonary dysplasia
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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 Increas
ed hemolysis
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Term Newborn Phase of Adaptation age birth up
to 1 month
Pathophysiology Sepsis Hyperbilirubinemia
Seizures Hypocalcemia Hypoglycemia Malformat
ions
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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)
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Infants and Toddler Phase of proliferation and
growth age 22 days to 24 months
Pathophysiology Otitis media Bronchiolitis
Febrile seizures Rickets
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Children Phase of Differentiation and
Training age 2 to 11 years Physiology Slowe
r growth rate Increased independence Increased
school performance Shift to logical operations
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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 Or
gan transplantations Epileptic
syndromes Obesity Diabetes
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Adolescents Sexual Maturation age 12 to 17
years Physiology Rapid body
changes growth spurt gonadal
growth Emotional instability
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Adolescents Sexual Maturation age 12 to 17
years Pathophysiology Acne
vulgaris Endocrine dysfunctions Accidence Se
xual transmitted diseases Drug
addiction Doping
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Adolescent 12 - 17 years
Pre-term Infant lt 36 weeks of gestation
Term Newborn Infant 0-27 days
Infant/Toddler 28 days -23 months
Child 2 - 11 years
Adaptation
Growth
Survival
Training
Maturation

Seyberth, in Pädiatrie, eds Speer/Gahr, 2005
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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
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• Agenda
• 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

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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
Kearns et al, NEJM 2003
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Drug Absorption

• Gastric emptying delayed in infants lt 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

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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

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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)

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Neonatal Analgesic Clearance Delayed

• Immature hepatic enzymes
• Decreased during first weeks of life
• Renal blood flow
• Glomerular filtration
• Tubular secretion

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Renal Clearance Compared to Adults

• Neonates - decreased
• Premature infants - decreased
• Toddlers - increased
• Children - increased

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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

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Pharmacokinetic Differences Term Preterm
Infants
Absorption ? Gastric HCI-production
? Bile flow ? Bacterial intestinal
growth ? Enterohepatic
circulation Distribution ? Body
water ? Body fat ? Muscular
mass ? Plasma protein binding Liver
metabolism ? Hydroxylation ?
Glucoronidation Renale excretion
? GFR ? Tubular function
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Dosage-principle in the NICU

• Given
• Result
• Examples

• Vd ?
• Clearance ?
• Loading dose (LD) ?
• Maintenance dose (MD) ?
• Phenobarbital, Phenytoin, Methylxanthine,
  Digoxin, Aminoglykoside, Indometacin
  Chloramphenicol, Furosemide

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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
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• Agenda
• 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

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Types of Pediatric Studies

• 0. 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

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FDA Pediatric Study Decision Tree

• Reasonable to assume (pediatrics vs adults)
• similar disease progression?
• similar response to intervention?

NO
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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 ? in glomelar filtration
  rate for renal function

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• Parameters Requested in PIPs (Clinical Study
  Form)
• 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).

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Endpoint Examples
Drug Indication Surrogate Endpoint
ACEi, ARB, ß-blockers Hypertension BP lowering effect (DBP vs. SBP)
Statins Hyperlipidemia LDL lowering effect
Atorvastatin Atherosclerosis in children with lupus Carotid IMT
Enalapril Infant Single Ventricle Growth
Mitral regurgitation post AVSD repair LV end-diastolic dimension Z-score
Sildenafil Pulmonary hypertension Exercise tolerance
Ataluren Duchennes muscular dystrophy 6 min walk test
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Operational Challenges Clinical Trials

• Recruitment consent of parents
• Rule of the thumb recruitment the easier the
  more severe the disease
• gt 90 of children with cancer participate in
  trials
• Parents associations can help recruiting

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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

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Blood Withdrawals

• 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!

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Informed Consent Assent

• Use different texts for different age groups
• From around 7 years on, child will understand
• Childs signature is not legally binding, but
  should be asked for as a token of respect
• Physician can override childs dissent if there
  are serious medical reasons

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Ethics Committees / IRBs

• 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

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Laboratory/ Central Laboratory

• 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

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• Agenda
• 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

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• Structures for Pediatric Clinical Research
• 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

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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
• Networks fulfilling all minimum criteria
• Networks currently undergoing clarification
• Networks currently not qualifying
• MCRN medicines for children research network

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• Category 1
• 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)

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• Category 2
• Children Leukemia Group (CLG) (EORTC)
• Network of Excellence for Research in Paediatric
  Clinical Care

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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 dInvestigations Pédiatriques Produits de
  Santé (RIPPS)
• Swedish Pediatric Society (BLF) 
• Paediatric Trial Network (AMIKI)
• Italian Neonatal Network (INN)

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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 (general) write PIP (EU) CROs, medical writers, regulatory/ pediatric consultants, medical writers
3 3. Design individual projects, e.g. clinical studies, preclinical test batteries, technical formulation development etc PedResearch Networks (EnprEMA) reg/ ped consultants, CROs
4 Execute individual projects PedResearch Networks (EnprEMA), CROs
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• Agenda
• Children are different from adults physiology
• Children are different from adults ADME
• Pediatric clinical trials
• Existing evolving structures for pediatric
  clinical trials
• Relevant guidelines

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• Relevant Guidelines
• 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

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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.

• http//www.ich.org/fileadmin/Public_Web_Site/ICH_
  Products/Guidelines/Efficacy/E11/Step4/E11_Guideli
  ne.pdf

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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.

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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

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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
Organised by
In partnership with
For further information, please visit www.efgcp.eu
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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

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Thank You For Your Attention!
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Back-Ups
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Released May 2010