Non-clinical studies for paediatric programmes Ulla Wändel Liminga, PhD Medical Products Agency

1. Non-clinical studies for paediatric programmes Ulla Wändel Liminga, PhD Medical Products Agency Uppsala, Sweden feb 07

2. Summary of presentation • Introduction • Regulatory guidance • Species Differences in Development • Considerations and Conclusions feb 07

3. Non-clinical testing in drug development • Pharmacology • Primary: ‘Proof of concept’ - support to intended clinical use • Secondary & Safety Pharmacology (CNS, CV, respiratory etc.) • Pharmacokinetics / Toxicokinetics • ‘key’ animal  human; extent of exposure • Acute and repeat dose toxicity (two species, >6-12 month) • Genotoxicity (in vitro, in vivo) • Reproductive and developmental toxicity • Carcinogenicity (two species, 24 months ) • Other (e.g. local tolerance; environmental risk) feb 07

4. Non-clinical studies in drug development Clinical trials /marketing authorisation in ANY human • Extensive non-clinical testing - described in a number of guidelines Why ADDITIONAL data for young populations? • Additional/other risks due to ’immature’ / growing organism ? • Children may be included earlier in drug development, before more extensive adult data available feb 07

5. Potential key organs /systems • Central nervous system • Immune system • Pulmonary system • Reproductive system • Skeletal system • Renal function feb 07

6. Current Regulatory Situation • ICH M3 (Non-clinical studies for conduct of human clinical trials) • Most relevant safety data usually from adult human exposure, should generally be available • Repeated dose toxicity; genotoxicity, reproductive/developmental toxicity • Juvenile animal toxicity studies - case-by-case basis • Detailed guidelines on juvenile toxicity testing • European Union • Draft Guideline - Consultation period ended April 06 • FDA • Guidance for Industry: Non-clinical Safety Evaluation of Pediatric Drug Products (Feb 2006) feb 07

7. EU Guideline * Juvenile toxicity studies may be justified when… • Potential effects on growth/development cannot be studied in standard non-clinical and/or clinical studies • Pharmacology affects developing organ(s) (intended age group?) • Available data indicate toxicity in developing systems • Address already known concerns further e.g. reversibility or aggravation; establish safety factors * On Need for Preclinical Testing of Human Pharmaceuticals in Juvenile animals EMEA/CPMP/SWP/169215/2005; version released for consultation feb 07

8. Key elements for Need for Juvenile Studies* • Intended/ likely use in children • Disease (only/mainly in pediatrics; seriousness) • Age of population • Age dependent development of major organs • Potential differences in pharmacology and/or toxicity profiles between mature and immature systems * EMEA/CPMP/SWP/169215/2005; version released for consultation feb 07

9. Key elements for Need for Juvenile Studies* • Comparison animal /human • Timing of dosing in relation to growth/development in children and juvenile animals • Exposure margins vs. human adult - low or high? • Existing data in animal/human (adult and young); same product, class * EMEA/CPMP/SWP/169215/2005; version released for consultation feb 07

10. Guidance on study conduct • Duration up to 13 weeks in rats; 9 months in dogs. • Route of administration • Species – one generally sufficient • Pharmacokinetics/Toxicokinetics • Dose selection • Endpoints • Some additional points • modified pre-postnatal study address (some) developmental toxicity issues? * EMEA/CPMP/SWP/169215/2005; version released for consultation feb 07

11. Species Differences in Development feb 07

12. Challenges… • Important differences in timing of developmental events at birth in experimental animals and humans must be recognised when designing and interpreting juvenile studies in relation to potential human risk. • Significant gaps remain in the knowledge for the comparative age of major organ development in laboratory animals compared with human. • International non-profit organisation (ILSI/HESI) : • Project on Role of Juvenile Animal Studies in Assessment of Paediatric Safety (published 2003) feb 07

13. Species Neonate Infant Child Adolescent Rat (week) 0-1 1-3 3-10 10+ Dog (month) 0-0.5 0.5-2 2-10 10+ Primate (year) 0-0.1 0.1-1 1-5 5+ Human (year) 0-0.1 0.1-2 2-12 12+ Weaning Species comparison Example Equivalent Ages feb 07

14. Completion 6 - 8 years 16 weeks Birth 3 weeks 3 weeks Species Human Dog Monkey Rat Mouse Onset GWK36 ? ? PND4 PND4 At Birth Beginning Beginning Completed Not Started Not Started Critical Period Birth - 2 years 0-16 weeks in utero 4 - 14 days 3 - 14 days Species Comparison Example Alveolar Development Modified from Zoetis, 1999 & Zoetis Birth Defects Research 2003 (part B), Vol. 68:121-124 feb 07

15. Species Comparison Example Lung development: Conclusion • Main lung development considered complete at 2 years of age in humans • Potential for local toxicity most critical in children <2 years of age • Rat and dog acceptable models for testing safety of inhaled drugs for paediatric population • The primate not suitable model for postnatal lung development Zoetis Birth Defects Research 2003 (part B), Vol. 68:121-124 feb 07

16. Conclusion • Changes occur faster in laboratory animals than in human due to their faster growth and maturation rate • Paediatric organs at highest risk are those that undergo significant postnatal development. The brain is a primary example. • The majority of development is complete in human by 2-years of age - learning is a major exception feb 07

17. Considerations and Conclusions feb 07

18. Considerations for juvenile toxicity studies • Is there an appropriate comparative species? • What systems undergo maturation and when, in animal models in relation to humans ? • Toxicological end points to be monitored critical. • Standard study design addressing all potential issues not feasible. Instead, focus specific organ systems that develop post-natally. • Consider practical limitations • e.g. feasibility to obtain adequate samples for analysis, particularly in rodents. feb 07

19. Conclusions • Need of study considered on case-by-case basis • Indication, patient population • Pharmacology, class effects • Available safety data (clinical/non-clinical) e.g. known target organ toxicity • Suspected effects on growth and/or development • Particular concern for long term exposure in relation to human developmental stages • Endpoints and duration of study based on individual case • Studies should include TK/PK assessment feb 07

20. Advice to MAHs Discuss with regulators ! feb 07