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Clinical and Operational Challenges of Paediatric Clinical Trials (Seminar) Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development & More klausrose.

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Presentation on theme: "Clinical and Operational Challenges of Paediatric Clinical Trials (Seminar) Dr. med. Klaus Rose, M.D., M.S. Pediatric Drug Development & More klausrose."— Presentation transcript:

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

2 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 2

3 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 3

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5 Physiology: Large body surface Increased skin permeability Reduced surfactant synthesis Aortopulmonary shunts Immaturity of the brain stem No ciruclatory autoregulation Incomplete retinal vascularisation Preterm Newborn: Phase of survival born at < 36 weeks of gestation

6 Pathophysiology: Respiratory distress Pulmonary hypertension Patent ductus arteriosus Apnea Intraventricular hemorrhage Retinopathy of prematurity (ROP) Bronchopulmonary dysplasia Very Preterm Newborn: Phase of survival born at < 36 weeks of gestation

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

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

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 Pathophysiology: Accidence Dysfunctions of the immune system: Asthma/allergy Juvenile rheumatoid arthritis Autoimmune diseases Neoplasm Hyperkinesia Enuresis Organ transplantations Epileptic syndromes Obesity Diabetes Children: Phase of Differentiation and Training age: 2 to 11 years

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 Pre-term Infant < 36 weeks of gestation Term Newborn Infant 0-27 days Infant/Toddler 28 days -23 months Child years Adolescent years Survival Survival Adaptation Adaptation Growth Training Maturation Maturation Seyberth, in Pädiatrie, eds Speer/Gahr, 2005

18 Age Groups as per ICH E 11 Term newborn infants ( days) Infants and toddlers (28 days to 23 months) Children ( years) Preterm newborn infants ( days) Adolescents 12-16/17 y

19 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 19

20 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 20

21 Kearns et al, NEJM 2003 ADME In Children 21

22 Drug Absorption 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

23 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

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 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

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

30 Toxicity Examples Early Infancy & Childhood Target/ OrganDrugEffect Teethtetracyclinesdiscoloration/ enamel dysplasia Genital tractcyclophosphamideinfertility/ovarian failure Immune systemtacrolimusLymphoproliferation, diabetes Heartantracyclines alkylating agents methylphenidate cardiotoxicity heart failure cardiovascular events e.g. myocardial infarction CNSphenobarbital glucocorticoides methylphenidate cisplatin attention and memory dysfunction cerebral palsy stroke hearing loss Kidneyfurosemidenephrocalcinosis Boneglucocorticoidsgrowth impairment

31 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 31

32 Types of Pediatric Studies 0. Extrapolation / Modelling & Simulation 1.PK/PD: not in healthy children  phase I only in pediatric patients! 2.Controlled clinical trials (Phase II – IV) -Active control -Placebo control -No control (e.g. rare diseases) 3.Diagnostic studies 4.Non-interventional studies: long-term observation; registries; epidemiological studies Other categorisation: regulatory vs. Investigator initiated clin trials

33 Reasonable to assume (pediatrics vs adults) 3 similar disease progression? 3 similar response to intervention? FDA Pediatric Study Decision Tree NO Is there a PD measurement** that can be use to predict efficacy? NO Conduct PK studies Conduct safety/efficacy trials* NO Conduct PK studies to achieve levels similar to adults Conduct safety trials YES Reasonable to assume similar concentration-response (C-R) in pediatrics and adults? YES TO BOTH Conduct PK/PD studies to get C-R for PD measurement Conduct PK studies to achieve target concentrations based on C-R YES Conduct safety trials

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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 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). 36

37 Endpoint Examples DrugIndicationSurrogate Endpoint ACEi, ARB, β- blockers HypertensionBP lowering effect (DBP vs. SBP) StatinsHyperlipidemiaLDL lowering effect AtorvastatinAtherosclerosis in children with lupus Carotid IMT EnalaprilInfant Single VentricleGrowth Mitral regurgitation post AVSD repair LV end-diastolic dimension Z-score SildenafilPulmonary hypertensionExercise tolerance AtalurenDuchenne’s muscular dystrophy 6 min walk test

38 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

39 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

40 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!

41 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

42 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

43 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

44 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 44

45 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 45

46 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 46

47 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) Paediatric Network of Clinical Investigation Centers - CICPed 47

48 Category 2 Children Leukemia Group (CLG) (EORTC) Network of Excellence for Research in Paediatric Clinical Care 48

49 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) 49

50 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 projectsPedResearch Networks (EnprEMA), CROs

51 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 51

52 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 52

53 53 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.” *

54 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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56 56 The Declaration of Helskinki Version 2008 Does not contain the words ‘child’ or ‘minor’ Addresses vulnerable and incompetent research subjects Relevant §s: 9 & 28

57 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 For further information, please visit Programme Committee: Gesine Bejeuhr, VfA (Association of Research- based 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 : JUST ANNOUNCED !

58 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 58

59 Thank You For Your Attention! 59

60 Back-Ups 60

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62 Released May 2010


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