1. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Drug Development for Children – Importance of Clinical Trials Ian Chi Kei Wong Professor of Paediatric Medicines Research Centre for Paediatric Pharmacy Research The School of Pharmacy, University of London “A cheerful heart is good medicine, but a crushed spirit dries up the bones. (Proverbs 17:22)”.

2. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Content Reasons for lack of paediatric medications research Formulation PK study Efficacy Safety

3. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Content Reasons for lack of paediatric medications research Formulation PK study Efficacy Safety

4. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Prescribing of unlicensed and off label medicines - hospital Up to 65% of drugs used for children in hospitals are not licensed for purpose

5. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Very small

6. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Very big Very Big

7. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research “Modern pediatric pharmacology is a sophisticated clinical discipline capable of carrying out the studies necessary for the safe and ethical evaluation of drugs in children.” (US National Institute of Health 1994)

8. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Real problems “Pursuit of such studies, however, is limited by the scarcity of available facilities in which to follow children receiving drugs and to collect data in a systematic way, as well as the insufficient number of qualified clinical investigators interested in this problem.” (NIH 1994)

9. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Real problems Finance Research capacity 1.Infrastructure 2.Researchers

10. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Content Reasons for lack of paediatric medications research Formulation PK study Efficacy Safety

11. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research

12. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Poor formulations in clinical trials Only 49% used a paediatric formulation 25% used tablets/capsules –Only 26% of these gave administration details Reliability and Validity?

13. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research The majority of medicines are not designed for Children Tablets –Solid dosage form –Many children cannot swallow tablets whole –Crush or cut tablets

14. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Even when using tablet cutters Splitting tablets causes inaccuracy Solution or Problem?

15. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research crushers Solution or Problem? Adalat Retard 10mg Tablets Tuleu 2005

16. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Significant? IM injection Oral syrup IM solution + apple juice for oral Crushed tablets + apple sauce for oral Notterman 1986

17. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Significant? Change the PD Formulation Change the PK

18. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Reasons for lack of paediatric medications research Formulation PK study Efficacy Safety

19. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research General Principles The disease process is similar in adults and paediatric patients. The outcome of therapy is likely to be comparable. Extrapolation from adult efficacy data may be appropriate. Pharmacokinetic data showing similarities to those observed in adults will be sufficient.

20. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research General Principles Pharmacokinetic studies support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendations.

21. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research General Principles Relative bioavailability comparisons of paediatric formulations with the adult oral formulation typically should be done in adults. Definitive pharmacokinetic studies for dose selection across the age ranges of paediatric patients should be conducted in the paediatric population.

22. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research General Principles Linear pharmacokinetics in adults, single- dose pharmacokinetic studies in the paediatric population may be sufficient. Any non-linearity in absorption, distribution, and elimination in adults and any difference in duration of effect between single and repeated dosing in adults would suggest the need for steady state studies in the paediatric population.

23. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Practical points The volume of blood withdrawn should be minimized Blood volumes should be justified in protocols Collection of routine, clinical blood samples Topical anesthesia to place IV catheters Indwelling catheters rather than repeated venepunctures for blood sampling

24. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Practical points Sensitive assays Sparse sampling approaches where each patient contributes as few as 2 to 4 observations at predetermined times to an overall “population area- under-the-curve”. Sampling time points derived from modeling of adult data.

25. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Example: diclofenac

26. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Content Reasons for lack of paediatric medications research Formulation PK study Efficacy Safety

27. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research General Principles The principles in study design, statistical considerations and choice of control groups in adults generally apply to paediatric efficacy studies.

28. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Specific for children It may be necessary to develop, validate, and employ different endpoints for specific age and developmental subgroups. Measurement of subjective symptoms such as pain requires different assessment instruments for patients of different ages.

29. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Specific for children Duration of the chronic disease and the developmental stage of the patient may affect the response. Many diseases in the preterm and term newborn infant are unique or have unique manifestations precluding extrapolation of efficacy from older paediatric patients and call for novel methods of outcome assessment.

30. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Content Reasons for lack of paediatric medications research Formulation PK study Efficacy Safety

31. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research General Principle Principles of adverse event reporting in adult population is generally applicable to paediatric studies.

32. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Specific points for children Age-appropriate, normal laboratory values and clinical measurements should be used in adverse event reporting Accidental ingestions or medication errors etc provide the opportunity to obtain safety and pharmacokinetic information.

33. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research Specific points for children Developing physiological systems may respond to drugs differently from matured adult. –Eg Tetracycline Some adverse events occur at a later stage Long-term studies or surveillance data may be needed to monitor the effect of developing systems. –Eg ADHD treatment

34. Great Ormond Street Hospital for Children NHS Trust The School of Pharmacy UCL INSTITUTE OF CHILD HEALTH Centre for Paediatric Pharmacy Research