1. Regulatory Experience Employing Extrapolation In Pediatric Drug Development William Rodriguez, M.D. Science Director of Pediatrics Office of Counter-Terrorism and Pediatric Drug Development

2. Pediatric Drug Development and Extrapolation  1979Labeling Required  1994 Final Pediatric Labeling – extrapolation of efficacy  1997 FDAMA/Exclusivity Provision  2002BPCA

3. The 1994 Rule  Required sponsors of marketed products to review existing data and submit appropriate labeling supplements  Applied to approved drugs and biologics  A pediatric indication may be based on adequate and well-controlled trials in adults with other information supporting pediatric use, e.g., PK and safety data  No requirement to perform new studies in pediatrics

4. When can Efficacy be extrapolated?  If the course of the disease and the effects of the drug, both beneficial and adverse, are sufficiently similar in the pediatric and adult populations,it may be permissible to extrapolate the adult and efficacy data to pediatric patients

5. Other Supporting Information  Further information developed in the appropriate pediatric group which supports the use in that group (s): at a minimum PK and safety must be obtained  Caveat: if PK parameters not well correlated with activity in adults, a clinical study would more likely be requested.

6. Types of Study (cont’d) : Pharmacokinetics/ Pharmacodynamics  An approach based only on PK is likely to be insufficient when blood levels are known or expected not to correspond with efficacy or when there is concern that concentration – response relationship vary with age – NEED studies of clinical or pharmacologic effects  If the comparability of the disease and outcome of therapy are similar, but appropriate blood levels not clear, a combined measurement PK/PD approach may be possible.

7. Extrapolation may not be the right approach  The adult efficacy cannot be extrapolated to the pediatric group  Response to a drug may differ because of receptor differences or disease manifestations being different  Difficulties may be posed by the child’s inability to cooperate:  with the delivery method or  with the use of instruments used to measure the same clinical endpoints (i.e. pulmonary function test)

8. Extrapolation may not be appropriate  Disease is different in etiology, pathophysiology and/or manifestations  Example: Unique pediatric epileptic syndrome(s): neonatal seizures; infantile spasms; febrile seizures neonatal seizures; infantile spasms; febrile seizures  Response to therapy is different  Example: Antiepileptic drugs effective in adults may be ineffective or proconvulsant in children i.e. phenytoin and carbamazepine may exacerbate certain pediatric seizure types; vigabatrin ( not approved in the USA) may exacerbate myoclonic seizures, or drugs can be ineffective in adults and therapeutic in children ( i.e. ACTH, steroids) or drugs can be ineffective in adults and therapeutic in children ( i.e. ACTH, steroids)  Pathophysiology may be comparable but response to therapy not predictably the same in adults and children  Psychotropics

9. Favorable Scenarios for Extrapolation (rather safe)  Drug effective in adults and in children down to 6 years of age In order to extend labeling down to 1 month - must establish must establish  disease is similar, response to treatment is similar  plasma levels of drug dosing is in therapeutic ranges  the safety profile is acceptable  Extrapolation has generally been appropriate in  Antimicrobials  Antiviralsdiseases shared by all ages  bronchodilators (oral)  AIDS

10. What is the nature of the evidence that could be used to extrapolate data to children?  Empirical comparisons  Knowledge of mechanisms  Known adult-child physiologic and clinical properties of analogous drugs  Known sensitivity of children to specific toxicities How do we get there?  Non-clinical studies  Pathophysiology  Similar Natural History in an affected population  Similarity of Response to therapy

11. Safety Data: Essential

12. Additional Supporting Evidence:  Pharmacokinetics  Exposure/Response

13. IndicationStudies neededDosage``Pediatric use`` Pediatric indication only (indication different than in adult) Adequate and well-controlled studies in pediatric population and will be described under "Indications and Usage" Under dosage and administra- tion  limitations on the pediatric indication (need for specific monitoring, specific hazards associated with use of the drug in any subsets of the pediatric population)  differences between pediatric and adult responses to the drug,  other information related to the safe and effective pediatric use of the drug Pediatric use for an indication also approved in adults Adequate and well-controlled studies in pediatric population and will be described under "Indications and Usage" Same as above Pediatric Studies and Labeling 21 CFR 201.57(f)(9)

14. Indica- tion Studies neededDosage``Pediatric use`` Pediatric use based on adult data Adequate and well-controlled studies in adults with other information supporting its pediatric use. Note: the course of the disease and the effects of the drug, both beneficial and adverse, are sufficiently similar in the adult and pediatric populations to permit extrapolation from the adult efficacy data to pediatrics. Additional information: PK for determination of appropriate dose, PD and/or other data to support safety and effectiveness in pediatric population As above Indicate use is supported by evidence from adequate and well- controlled studies in adults with additional data (supporting effectiveness in pediatric population). Pediatric Studies and Labeling 21 CFR 201.57(f)(9) (cont.)

15. Reasonable to assume (pediatrics vs adults) 3 similar disease progression? 3 similar response to intervention? 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

16. Questions for Pediatric Studies  What is the public health benefit for using the product in children?  For what ages?  What information is needed?  What other products are available/approved for this indication?  What types of studies are being done (or should be conducted)?

17. Studies Breakdown report for Issued Written Requests (4 points in time) Pediatric Exclusivity as of: Type of Study 5/1/995/1/009/30/029/3/03 N (%) Efficacy & Safety 63 (37) 113 (38) 210 (35) 230 (35) PK & Safety 58 (34) 86 (29) 181 (30) 196 (30) PK/PD 10 (6) 26 (9) 56 (9) 58 (9) Safety 26 (15) 66 (22) 98 (16) 104 (15) Other 14 (8) 7 (2) 56 (9) 72 (11) Total171298601660 WR Issued 76145256284

18. EXPERIENCES

19. Psychotropics: An Experience (Buspirone)  Indications:-adult Generalized Anxiety Disorder  Pathophysiology: symptoms same as adults  History: continuity across age span but not usually manifested (dx) below age 6 years  Response: improvement in same clinical signs and sx used for diagnosis of adults  Studies: (a) 2 multi center randomized double blind placebo controlled-studies to evaluate efficacy & safety- (b) PK open-labeled dose escalation (b) PK open-labeled dose escalation  Results: safety & effectiveness not established in patients 6-17 years at doses recommended for use in adults-PK parameter (AUC / Cmax) of drug found to be equal to or higher in children and adolescents than that in adults.

20. Psychotropics: An Experience (Fluvoxamine)  Indications: - obsessive compulsive disorder  Pathophysiology: symptoms the same as adults  History: continuity across age span not usually dx below 6 years of age  Response: Improvement in same clinical signs and symptoms used for diagnosis of adults  Studies: (a) multicenter/open label PK study,  (b) long term open label safety study  Results: dose adjustment (increased dose) may be necessary in adolescents, and girls 8-11 years of age may require lower dose

21. Antiepileptics: An Experience (Gabapentin)  Indication: epilepsy/partial seizures  Pathophysiology: clinical and symptom markers used for diagnosis similar for all ages  History - continuity across age span  Response - Improvement in same clinical signs and symptoms as used for diagnosis of adults  Studies - (a) double-blind random placebo controlled, parallel group efficacy and safety study as add-on therapy (b) population PK, (c) open label extension study, (d) single dose PK

22. Antiepileptics: An Experience (continued)  Results - safety and effectiveness down to 3 years neuropsychiatric AE’s identified in 3-12 yr old; oral clearance (normalized by body weight) increased in children < 5 yrs; higher doses required in children < 5 yrs

23. Cardiovascular: An Experience (Enalapril)  Indication: hypertension  Pathophysiology: clinical and sx markers used for diagnosis for all ages  History - course in prepubertals may differ from adolescents and adults  Response - improvement in same clinical signs and symptoms as used for the dx in adults  Studies - (a) open label PK study -(b) double blind, dose response study  Results - Labeling for 1 mo. - 16 yrs of age, info. on dose, efficacy and pharmacokinetics - information on preparation of a suspension

24. Cardiovascular: an experience (Fosinopril)  Indication - Hypertension  Pathophysiology -Symptoms same as adult  History – course in prepubertal may differ from adolescent and adults  Responses – improvement in same clinical signs and symptoms used for the dx of adult  Studies –  open label, multicenter, single dose PK study (1 mo–16 yrs)  Multicenter, randomized, double blind dose ranging and placebo controlled study (6-16 yrs)  Results –  New recommended dose in children weighing more than 50 kg.  New information on PK parameters  An appropriate dose strength is not available for children weighing less than 50 kg.

25. The Conduct of Pediatric Studies: What have We learned in the area of Pharmacokinetic/Pharmacodynamics Some examples Produces Some populations may need to start therapy at lower end of dosing to avoid AE Midazolam hydrochloride Elimination ½ life may be shorter in pediatric patients than adults Atovaquone/proguanil Volume of distribution and ½ life may differ in a fashion which necessitates doses higher in younger children than adults Etodolac

26. The Conduct of Pediatric Studies: What have We learned in the area of Pharmacokinetic/Pharmacodynamics (cont.) Some examples (cont.) Higher oral clearance by body weight in patients < 5 yrs necessitated higher dose Gabapentin Body surface area is more important covariant and more relevant than age Sotalol hydrochloride Pharmacokinetic parameters (area under the curve and maximum concentration of drug) may be equal to or higher in children and adolescents than in adults and no demonstrated efficacy Buspirone hydrochloride

27. What are the Gaps in Information?  Many populations such as infants, neonates both term and pre-term remain to be studied  Still a lot to be learned in terms of clear E-R relationship across the various special populations.  Development of appropriate pediatric formulations