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Drugs for children

Drugs for children. Irja Lutsar Tallinn 2007. Pediatrics does not deal with miniature men and women, with reduced doses the same class of disease in smaller bodies, but ….. has its own independent range and horizon. Abraham Jacobi rohkem kui 100 aastat tagasi.

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Drugs for children

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  1. Drugs for children Irja Lutsar Tallinn 2007

  2. Pediatrics does not deal with miniature men and women, with reduced doses the same class of disease in smaller bodies, but ….. has its own independent range and horizon Abraham Jacobi rohkem kui 100 aastat tagasi

  3. Problem statement: child vs adult • The effectiveness and tolerabily is likely to be different • Neonates (premature and full-term) - < 28 days • Infants – 1 mo - < 2years • Children – 2 years – 11 years • Adolescents – 12 years – 16 (-17) years • Dose cannot be directly extrapolated from adults • Different pharmacokinetics • absorption • distribution • elimination • Many agents used in paediatric are never tested in children

  4. Pharmacokinetics of pencillin G Metsvaht et al. AAC 2007; 51: 1995-00

  5. Mean voriconazole plasma concentrations after IV and POS administration BA in adults 96% Walsh et al. AAC 2007

  6. Formulations not suitable for children • IV formulation toxic or too concentrated • Cyclodextran & nephrotoxic • Quinolones are reconstituted in acids • Not suitable presentations (too large or too small vials) • Oral formulations • Capsules and film-coated tablets (children cannot swallow) • Crushed tablets vs whole tablets • How to give bitter tablets? • Solution and suspensions • Better solubility worse taste • What is a good taste? • Should a medicine have a good taste? • Too large amounts • Bioavailability

  7. Crushed tablet Slow release tablet

  8. History • 1937 – 107 people with streptococcal infection died (mainly children) • All were treated with a sulphonamide that was diluted in diethylglycole (antifris) • 1956 – neonates who received sulphonamides had more often kernicterus than those receiving tetracycline • Chloramphenicol & “gray baby syndrome” (enzyme immaturity) • “Gasping syndrome” • Agents that are reconstituted in benzylalcochol (IV clindamycin) • Antidepressants

  9. How common is off-label use Then younger the child then lower number of studies Then sicker the child the less studies Eur J Pediatr 2005; 164: 552-558

  10. Studies in children: statistics • 1997 – FDA 33 new drugs licenced • 27 potentially used for children • 9 had some information on use in children • Neonates use a lot of medicines • Detroit (USA) 1997-2004 NICU 3,6/per child • ELBW - 11,7/per child • Australia 93% ELBW at least 1 untested drug will be used

  11. FDA: paediatric studies • FDAMA Pediatric Exclusivity 1997 (voluntary) • Pediatric Rule Regulation 1998 (enjoined 2002) • January 2002 - FDAMA Exclusivity Sunsets • January 2002 (compulsary) - Best Pharmaceuticals for Children Act (BPCA) • December 2003 - Pediatric Research Equity Act (PREA) • October 2007: Sunset for BPCA & PREA

  12. All new drugs ned to be tested in children Industry initiated (WR) waivers Disease does not exsist in children Drug is too toxic for children Deferral until more data on adults are available Patent prodection for 6 months Fluconazole 600 mill $ Sildenafil 1 bill $ FDA: stick (WR) & carrot (PE) Priotrity list of medicines

  13. FDA: results (March 2007) • FDA issued 341 WR • 150 new medicines were tested in children • 128 labelling changes were made

  14. Benefits of WR (FDA) • 1998- 2004 – 253 studies in children with new agents • 125 (50%) – efficacy • 51 (20%) – MD PK • 34 (13%) – SD PK • 43 (17%) – safety & tolerability • 127 (50%) new information • 113 (45%) published • Net economic return - -8,9 mil....507.9 mil $ JAMA 2006; 296: 120-123 JAMA 2007; 297: 480-8

  15. FDA: 127 changes in drug information • New dose or changes in exsisting dose (n = 25) • New data on tolerability (n = 35) • “No data in children” added into label (n = 28) • New dosing recommendations for infants or neonates (n = 83)

  16. We got know what we do not know Many questions were answered but many mopre questions raised

  17. Deficiencies in the FDA regulations • Industry might not be interested • Pediatric market is small • Studies in children are complicated • Long-lasting negotiations • No procedure to study off patent drugs • No paediatric trial registry

  18. European Union The same issues

  19. Paediatric regulation:entered into force 26 January 2007 • Improve the health of children • Increase high quality, ethical research intomedicines for children • Increase availability of authorised medicines forchildren • Increase information on medicines • Achieve the above • Without unnecessary studies in children • Without delaying authorisation for adults

  20. Main pillars of the Regulation • New EMEA Committee: the Paediatric Committee • An agreed (evolutive) paediatric development: the Paediatric Investigation Plan (PIP) • A mix of rewards and incentives • For on-patent products • For off-patent products • A series of other tools for information, transparency, and stimulation of research

  21. Paediatric Committee (PDCO) to be established by 26 July 2007 CHMP members (5) Patient/family and health- care professionals (6) Experts from National Competent Authorities (22) + EEA + alternates

  22. Paediatric committe: objectives • Paediatric scientific advice • Free of charge • Not binding • Review of PIPs (+waivers & deferrals) • Member States Survey of all existing uses of medicinal products in children, including off-label within 2 years, final EMEA inventory in third year (2009) • Update of Paediatric needs by Paediatric Committee on basis of inventory

  23. Currently unauthorised products18 months after entry into force of the Regulation, 26.07 2008 • Stick • Obligation to submit results of agreedPIP at time ofmarketing authorisation application • If not: Invalid application for MA • Results reported in SmPC • Authorisation in all Member States • Carrot • 6-month extension of the Supplementary Protection Certificate

  24. Patent-protected authorisedproducts 24 months after entry into force of the Regulation, 26.01 2009 • Stick • Obligation to submit results of agreed PIP at time of change (variation/extension) for new indication, route of administration, or pharmaceutical form • Results reported in SmPC • Authorisation in all Member States • Carrot • 6-month extension of the Supplementary Protection Certificate

  25. For off-patent products • Paediatric Use Marketing Authorisation (PUMA) New type of MA • Covers exclusively paediatric indication(s) andformulation(s) • Optional but need for PIP and compliance • No need for MA in all Member States • Brand name may be retained Carrot • 10 years of data protection: (8+2) +1

  26. Paediatric Investigation Plan • General strategy of paediatric studies • Epidemiology, pathophysiology, indications, target population, doses • New formulations (needs & technology) • Preclinical studies (toxicity, effect on pregnancy, young animals) • Clinical studies (PK studies, efficacy/safety studies, strategy, time-table) • Waivers and deferrals

  27. Time-table for paediatric studies CHMP NCA Scientific advice Non-clin Phase 1 Phase 2 Phase 3 MA Post approval 1 Compliance Deferral (annual report on progress) Waiver Amendments Paediatric invest. plan (PIP) PDCO

  28. Waivers • Product likely to be ineffective or unsafe in all or part of the paediatric population • Disease occurs only in adults • No significant therapeutic benefit over existing treatments for children → for one or more subgroups of the paediatric population → for one or more specified indications

  29. Deferrals • Request to defer initiation or completion ofsome or all the measures set out in the PIP • On initiative from applicant or Committee • For all or part of Paediatric Investigation Plan • Annual report to monitor deferred studies

  30. A European Network EMEA paediatric research network • To link together existing networks, investigators and centres with specific paediatric expertise • Build up competences at a European level • Facilitate the conduct of studies • Avoid duplication of studies Preparatory work at EMEA over 2005-6

  31. Paediatric studies are not the private business of the pharmaceutical industry

  32. Types of paediatric studies • Direct clinical studies • PK studies • Efficacy and toleration studies • Preclinical and non-clinical studies • Indirect studies • Assessment of paediatric standards • Growth and development • Epidemiological studies • Prevalence of the disease in children • Pathomechanism of the disease • Investigations on growth, development & maturation

  33. Who should conduct studies in children • Pharmaceutical industry • Universities, research institutes, medical schools • All paediatricians – why not?

  34. Who should fund paediatric studies • Pharmaceutical industry • Pharmaceutical industry + private funds • EU governmental funds (research councils, science boards) • EU grants • EU 7FP specific call for paediatric studies for off-patent used drugs • Priority list • Paediatric Societies • Charities • Bill & Melinda Gates foundation

  35. Other Measures:Funding of studies into off-patent medicines for children • Community funding • Liaison with EC (DG Research) for calls for proposals under the 7th framework programme (special programme for off-patent drugs) • Priority list of off-patent medicinal products for paediatric studies (published in December 2006 for comments till 31 January 2007- Finalisation at the March Paediatric Working Party)

  36. Paediatric studies – how to start?

  37. Questions to answer first? • Does the disease occur in paediatrics? • How common is the disease in paediatrics? • Common → continue • Rare → ??? • Is there an unmet medical need? • Yes → continue • Which are the potential paediatric indications? • Similar to adults • Different of adults • Is the disaese process in children and adults similar? • Infections – yes • Fever – yes • Seizures – unknown • HIV - no

  38. Planning is the key • Which studies when and how • Non-clinical studies (toxicity, juvenile animals) • Formulation issues –child friendly • suspension, solution • Taste and amount • IV formulation (concentration??) • Veins are narrow • Limited amount of fluid could be given • Bioavailability • Safety/efficacy in all paediatric populations

  39. Pediatric Study Decision Tree NO YES TO BOTH Reasonable to assume similar concentration-response (C-R) in pediatrics and adults? • Conduct PK studies • Conduct safety/efficacy trials* YES NO NO • 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 safetytrials • Reasonable to assume (pediatrics vs adults) • similar disease progression? • similar response to intervention?

  40. PK established in all paediatric populations Safety well described Efficacy can be extrapolated from adults Child-friendly formulation available Post-marketing experience No need for further paediatric studies Studies with new formulation could be performed in adults An ideal drug

  41. Unmet medical need & some paediatric data • Pharmacokinetic studies • Linear pharmacokinetics – SD studies • Non-linear pharmacokinetics – MD studies • Target concentration • Safety studies if efficacy can be extrapolated from adults • Efficacy studies if efficacy cannot be extrapolated from adults • Step-down timing • Studies in adults and in older children first • Do not forget neonates, if there is a need

  42. PK Exposures in Paediatrics and Adults 1.33 fold dose inc. 2.78 fold 1.33 fold * 35 subjects from SD and MD PK studies ** 236 healthy volunteers from SD and MD PK studies

  43. Ethical issues • Is it ethical to conduct studies in children? • Is it ethical not to conduct studies in children? • Points to consider • Sample size • Pain and dyscomfort • Informed consent and assent • Blood loss • No investigations for study purposes only • Effect on growth and development • Is there a benefit (for this child, for the group of children with similar disease) • Healthy volunteers are not accepted

  44. Kuidas Eesti saaks osaleda laste uuringutes • Kui palju Eestis kasutatavaid ravimeid omab andmeid kõigi eagruppide kohta? • Uuringute register lastearstide seltsi juures • Farmaatsiatööstuse poolt läbiviidavad uuringud pole ainukesed kliinilised uuringud lastel • EU grandid koos kolleegidega Euroopast • EV valitsus - ETF, sihtfinatseerimine • Heategevuslikud fondid (nt. Lastefond jne) • Rahva teavitamine • Miks ja kuidas teostatakse uuringuid lastel

  45. Summary • Political decision - there is a need for more paeditaric data • Each day new paediatric data will be released • Future - All medicines used in children should have paediatric data

  46. Pediaatrilised uuringud on globaalsed • Luua sidemed 3-ndate riikide andmebaasidega • Lasteuuringute andmebaas kõigile veebis kättesaadavaks

  47. Compliance check:Possible scenarios (new products) PIPDecision Waiver Completion of Measures at MAA Deferral MA validation MA Partial deferral Completion measures Annual reports on deferral Completion measures Partial completion measures Annual reports on deferral Reward : If compliant + Results in SPC + Authorisation in all MSs Compliance check

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