Clinical and Operational Challenges of Paediatric Clinical Trials (Seminar)

1. 34th EMWA Conference Clinical and Operational Challenges of Paediatric Clinical Trials (Seminar) Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development & Moreklausrose Consultingklaus.rose@klausrose.net

2. Agenda • Childrenare different fromadults: physiology • Childrenare different fromadults: ADME • Pediatricclinicaltrials • Existing & evolvingstructuresforpediatricclinicaltrials • Relevant international guidelines klaus.rose@klausrose.net

3. Agenda • Childrenare different fromadults: physiology • Childrenare different fromadults: ADME • Pediatricclinicaltrials • Existing & evolvingstructuresforpediatricclinicaltrials • Relevant international guidelines klaus.rose@klausrose.net

5. 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

6. 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

8. 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

9. Term Newborn: Phase of Adaptation age: birth up to 1 month Pathophysiology: Sepsis Hyperbilirubinemia Seizures Hypocalcemia Hypoglycemia Malformations

11. 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)

12. Infants and Toddler: Phase of proliferation and growth age: 22 days to 24 months Pathophysiology: Otitis media Bronchiolitis Febrile seizures Rickets

13. Children: Phase of Differentiation and Training age: 2 to 11 years Physiology: Slower growth rate Increased independence Increased school performance Shift to logical operations

14. 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

15. Adolescents: Sexual Maturation age: 12 to 17 years Physiology: Rapid body changes: growth spurt gonadal growth Emotional instability

16. Adolescents: Sexual Maturation age: 12 to 17 years Pathophysiology: Acne vulgaris Endocrine dysfunctions Accidence Sexual transmitted diseases Drug addiction Doping

17. Adolescent 12 - 17 years Pre-term Infant < 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

18. 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

19. Agenda • Childrenare different fromadults: physiology • Childrenare different fromadults: ADMET • Pediatricclinicaltrials • Existing & evolvingstructuresforpediatricclinicaltrials • Relevant international guidelines klaus.rose@klausrose.net

20. Key Publication Kearns, 2003, NEJM • Absorption, Distribution, Metabolization, Excretion in childrenare different fromadults • Maturationwithageis not linear and not in parallel • Variabilitymuchhigher

21. ADME In Children Kearns et al, NEJM 2003

22. 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 Drug Absorption

23. 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: Protein binding lower in newborns

24. 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)

25. Neonatal Analgesic Clearance Delayed • Immature hepatic enzymes • Decreased during first weeks of life: • Renal blood flow • Glomerular filtration • Tubular secretion

26. Renal Clearance Compared to Adults: • Neonates - decreased • Premature infants - decreased • Toddlers - increased • Children - increased

27. 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 Renal Elimination

28. 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

29. Given: Result: Examples: Vd  Clearance  Loading dose (LD)  Maintenance dose (MD)  Phenobarbital, Phenytoin, Methylxanthine, Digoxin, Aminoglykoside, Indometacin Chloramphenicol, Furosemide Dosage-principle in the NICU

30. Toxicity Examples Early Infancy & Childhood

31. Agenda • Childrenare different fromadults: physiology • Childrenare different fromadults: ADME • Pediatricclinicaltrials • Existing & evolvingstructuresforpediatricclinicaltrials • Relevant international guidelines klaus.rose@klausrose.net

32. Types of Pediatric Studies • 0. Extrapolation / Modelling & Simulation • PK/PD: not in healthychildren phase I only in pediatricpatients! • Controlledclinicaltrials (Phase II – IV) • Activecontrol • Placebo control • Nocontrol (e.g. rare diseases) • Diagnosticstudies • Non-interventionalstudies: long-term observation; registries; epidemiologicalstudies • Other categorisation: regulatory vs. Investigatorinitiatedclintrials

33. FDA Pediatric Study Decision Tree YES TO BOTH NO Reasonable to assume similar concentration-response (C-R) in pediatrics and adults? • Conduct PK studies • Conduct safety/efficacy trials* NO YES • Conduct PK studies to achieve levels similar to adults • Conduct safety trials Is there a PD measurement** that can be use to predict efficacy? YES • Conduct PK/PD studies to get C-R for PD measurement • Conduct PK studies to achievetarget concentrations based on C-R • Conduct safety trials • Reasonable to assume (pediatrics vs adults) • similar disease progression? • similar response to intervention? NO

34. klaus.rose@klausrose.net

35. 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

36. Parameters Requested in PIPs (Clinical Study Form) • Type ofstudy& study design • Type of control (placebo/ active control), justification, • Location (regions), • Test products; dose; route of administration, • Objective(s) ofthestudy, • Number of patients (M/F) and per age group • Duration of treatment (incl post-study observation ) • Main inclusion/exclusioncriteria, • 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

37. Endpoint Examples

38. 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

39. 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 Operational Challenges Clinical Trials

40. 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! Blood Withdrawals

41. 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 Informed Consent & Assent

42. 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 Ethics Committees / IRBs

43. 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 Laboratory/ Central Laboratory

44. Agenda • Childrenare different fromadults: physiology • Childrenare different fromadults: ADME • Pediatricclinicaltrials • Existing & evolvingstructuresforpediatricclinicaltrials • Relevant international guidelines klaus.rose@klausrose.net

45. StructuresforPediatric Clinical Research • EU networkofnetworks: EnprEMA • Commercial CROs • Further academicresearchnetworks • National, European, US-American and International disease-specificacademicnetworks • ESDP (European Society ofDevelopmentalPharmacology) • ICDRA (International Conference of Drug RegulatryAuthorities), coordinatedby WHO klaus.rose@klausrose.net

46. European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) • Academic clinicalnetworks, coordinatedby EMA • On EMA website: Enpr-EMA workshops; • Threemembershipcategories • Networks fulfilling all minimumcriteria • Networks currentlyundergoingclarification • Networks currently not qualifying • MCRN: medicinesforchildrenresearchnetwork klaus.rose@klausrose.net

47. Category 1 • European CysticFibrosis Society Clinical Trials Network (ECFS-CTN) • European Network forHyperkineticDisorders (EUNETHYDIS) • European PaedOncology Off-patent MedicinesConsortium (EPOC) • FinnishInvestigators Network forPediatricMedicine (FINPEDMED) • German Neonatal Network (GNN) • Innovative TherapiesforChildrenwithCancer (ITCC) • International BFM Study Group (I-BFM-SG) • ItalianPaediatricFederation MCRN (FIMP - MCRN) • MCRN The Netherlands (MCRN NL) • Mother Infant Child Youth Research Network, Canada (MICYRN) • NIHR MedicinesforChildren Research Network (MCRN UK) • Newcastle CCLG Pharmacology Studies Group • Paediatric European Network forthe Treatment of AIDS (PENTA) • PediatricRheumatology International Trials Organisation (PRINTO) • Scottish MCRN (Scotmcn) • United KingdomPaediatricVaccines Group (UKPVG) • European Group for Blood andMarrow Transplantation (EBMT) • Paediatric Network of Clinical Investigation Centers - CICPed klaus.rose@klausrose.net

48. Category 2 • Children Leukemia Group (CLG) (EORTC) • Network of Excellence for Research in Paediatric Clinical Care klaus.rose@klausrose.net

49. Category 3 • BelgianPediatric Drug Network – BPDN • EuroNeoNet • EurSocPaedGastronenterology, Hepatol & Nutr (ESPGHAN) • Futurenest Clinical Research • International Pediatric Transplant Association (IPTA) • IrishPaediatric Clinical Research Network (IPCRN) • JuvScleroerma Working Group - PaedRheumatologyEurSoc • National Center Child Healthand Development (NCCHD) Japan • Neocirculation • Paed European Network forthe Treatment ofInfection (PENTI) • Réseaud’InvestigationsPédiatriquesProduits de Santé (RIPPS) • SwedishPediatric Society (BLF)  • Paediatric Trial Network (AMIKI) • ItalianNeonatal Network (INN) klaus.rose@klausrose.net

50. Levels OfExternal Support In Pediatric Drug Development