Regulatory Experience Regulatory Experience Employing ExtrapolationEmploying Extrapolation

In In Pediatric Drug Pediatric Drug DevelopmentDevelopment

William Rodriguez, M.D.William Rodriguez, M.D.Science Director of PediatricsScience Director of Pediatrics

Office of Counter-Terrorism and Office of Counter-Terrorism and Pediatric Drug DevelopmentPediatric Drug Development

Pediatric Drug Development and Pediatric Drug Development and ExtrapolationExtrapolation

19791979 Labeling RequiredLabeling Required 1994 1994 Final Pediatric Labeling – Final Pediatric Labeling –

extrapolation of efficacyextrapolation of efficacy 1997 1997 FDAMA/Exclusivity ProvisionFDAMA/Exclusivity Provision 20022002 BPCABPCA

The 1994 RuleThe 1994 Rule

Required sponsors of marketed products to review Required sponsors of marketed products to review existing data and submit appropriate labeling existing data and submit appropriate labeling supplementssupplements

Applied to approved drugs and biologicsApplied to approved drugs and biologics A pediatric indication may be based on adequate and A pediatric indication may be based on adequate and

well-controlled trials in adults with other information well-controlled trials in adults with other information supporting pediatric use, e.g., PK and safety datasupporting pediatric use, e.g., PK and safety data

No requirement to perform new studies in pediatricsNo requirement to perform new studies in pediatrics

When can Efficacy be When can Efficacy be extrapolated?extrapolated?

If the course of the disease and the effects of If the course of the disease and the effects of the drug, both beneficial and adverse, are the drug, both beneficial and adverse, are sufficiently similar in the pediatric and adult sufficiently similar in the pediatric and adult populations,it may be permissible to populations,it may be permissible to extrapolate the adult and efficacy data to extrapolate the adult and efficacy data to pediatric patientspediatric patients

Other Supporting InformationOther Supporting Information

Further information developed in the appropriate Further information developed in the appropriate pediatric group which supports the use in that pediatric group which supports the use in that group (s): at a minimum PK and safety must be group (s): at a minimum PK and safety must be obtainedobtained

Caveat: if PK parameters not well correlated with Caveat: if PK parameters not well correlated with activity in adults, a clinical study would more activity in adults, a clinical study would more likely be requested.likely be requested.

Types of Study Types of Study (cont’d)(cont’d) : : Pharmacokinetics/ PharmacodynamicsPharmacokinetics/ Pharmacodynamics An approach based only on PK is likely to be An approach based only on PK is likely to be

insufficient when blood levels are known or expected insufficient when blood levels are known or expected not to correspond with efficacy or when there is not to correspond with efficacy or when there is concern that concentration – response relationship concern that concentration – response relationship vary with age – NEED studies of clinical or vary with age – NEED studies of clinical or pharmacologic effectspharmacologic effects

If the comparability of the disease and outcome of If the comparability of the disease and outcome of therapy are similar, but appropriate blood levels not therapy are similar, but appropriate blood levels not clear, a combined measurement PK/PD approach may clear, a combined measurement PK/PD approach may be possible.be possible.

Extrapolation may not be the Extrapolation may not be the right approachright approach

The adult efficacy cannot be extrapolated to The adult efficacy cannot be extrapolated to the pediatric groupthe pediatric group Response to a drug may differ because of receptor Response to a drug may differ because of receptor

differences or disease manifestations being differences or disease manifestations being differentdifferent

Difficulties may be posed by the child’s inability Difficulties may be posed by the child’s inability to cooperate:to cooperate: with the delivery method or with the delivery method or with the use of instruments used to measure the same with the use of instruments used to measure the same

clinical endpoints (i.e. pulmonary function test) clinical endpoints (i.e. pulmonary function test)

Extrapolation may not be appropriateExtrapolation may not be appropriate Disease is different in etiology, pathophysiology and/or Disease is different in etiology, pathophysiology and/or

manifestationsmanifestations Example: Unique pediatric epileptic syndrome(s):Example: Unique pediatric epileptic syndrome(s):

neonatal seizures; infantile spasms; febrile seizuresneonatal seizures; infantile spasms; febrile seizures

Response to therapy is differentResponse to therapy is different Example: Antiepileptic drugs effective in adults may be Example: Antiepileptic drugs effective in adults may be

ineffective or proconvulsant in children i.e. phenytoin and ineffective or proconvulsant in children i.e. phenytoin and carbamazepine may exacerbate certain pediatric seizure carbamazepine may exacerbate certain pediatric seizure types; vigabatrin ( not approved in the USA) may exacerbate types; vigabatrin ( not approved in the USA) may exacerbate myoclonic seizures,myoclonic seizures,

or drugs can be ineffective in adults and therapeutic in or drugs can be ineffective in adults and therapeutic in children ( i.e. ACTH, steroids)children ( i.e. ACTH, steroids)

Pathophysiology may be comparable but response to therapy not Pathophysiology may be comparable but response to therapy not predictably the same in adults and childrenpredictably the same in adults and children PsychotropicsPsychotropics

Favorable Scenarios for ExtrapolationFavorable Scenarios for Extrapolation(rather safe)(rather safe)

Drug effective in adults and in children down to 6 years Drug effective in adults and in children down to 6 years of ageof ageIn order to extend labeling down to 1 month - In order to extend labeling down to 1 month -

must establishmust establish disease is similar, response to treatment is similardisease is similar, response to treatment is similar plasma levels of drug dosing is in therapeutic rangesplasma levels of drug dosing is in therapeutic ranges the safety profile is acceptablethe safety profile is acceptable

Extrapolation has generally been appropriate inExtrapolation has generally been appropriate in Antimicrobials Antimicrobials AntiviralsAntivirals diseases shared by all agesdiseases shared by all ages bronchodilators (oral)bronchodilators (oral) AIDSAIDS

What is the nature of the evidence that could What is the nature of the evidence that could be used to extrapolate data to children?be used to extrapolate data to children?

Empirical comparisonsEmpirical comparisons Knowledge of mechanismsKnowledge of mechanisms Known adult-child physiologic and clinical Known adult-child physiologic and clinical

properties of analogous drugsproperties of analogous drugs Known sensitivity of children to specific toxicitiesKnown sensitivity of children to specific toxicities

How do we get there?How do we get there? Non-clinical studiesNon-clinical studies PathophysiologyPathophysiology Similar Natural History in an affected populationSimilar Natural History in an affected population Similarity of Response to therapySimilarity of Response to therapy

Safety Data: EssentialSafety Data: Essential

Additional Supporting Additional Supporting Evidence:Evidence:

PharmacokineticsPharmacokinetics

Exposure/ResponseExposure/Response

Indication Studies needed Dosage ``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

Same as above

Pediatric Studies and LabelingPediatric Studies and Labeling21 CFR 201.57(f)(9)21 CFR 201.57(f)(9)

Indica-tion

Studies needed Dosage ``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 LabelingPediatric Studies and Labeling21 CFR 201.57(f)(9) 21 CFR 201.57(f)(9) (cont.)(cont.)

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

Pediatric Study Decision TreePediatric Study Decision Tree

NO

Is there a PD measurement**that can be use to predictefficacy?

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 similarconcentration-response (C-R)in pediatrics and adults?

YES TO BOTH

•Conduct PK/PD studies to getC-R for PD measurement•Conduct PK studies to achievetarget concentrations based on C-R

YES

•Conduct safety trials

Questions for Pediatric StudiesQuestions for Pediatric Studies

What is the public health benefit for using What is the public health benefit for using the product in children? the product in children?

For what ages?For what ages? What information is needed?What information is needed? What other products are What other products are

available/approved for this indication?available/approved for this indication? What types of studies are being done (or What types of studies are being done (or

should be conducted)?should be conducted)?

Studies Breakdown report for Issued Written Studies Breakdown report for Issued Written Requests (4 points in time) Pediatric Requests (4 points in time) Pediatric

Exclusivity as of: Exclusivity as of: Type of StudyType of Study 5/1/995/1/99 5/1/005/1/00 9/30/029/30/02 9/3/039/3/03

N (%)N (%) N (%)N (%) N (%)N (%) N (%)N (%)

Efficacy & Efficacy & SafetySafety

63 (37)63 (37) 113 (38)113 (38) 210 (35)210 (35) 230 (35)230 (35)

PK & SafetyPK & Safety 58 (34)58 (34) 86 (29)86 (29) 181 (30)181 (30) 196 (30)196 (30)

PK/PDPK/PD 10 (6)10 (6) 26 (9)26 (9) 56 (9)56 (9) 58 (9)58 (9)

SafetySafety 26 (15)26 (15) 66 (22)66 (22) 98 (16)98 (16) 104 (15)104 (15)

OtherOther 14 (8)14 (8) 7 (2)7 (2) 56 (9)56 (9) 72 (11)72 (11)

TotalTotal 171171 298298 601601 660660

WR IssuedWR Issued 7676 145145 256256 284284

EXPERIENCESEXPERIENCES

Psychotropics: An ExperiencePsychotropics: An Experience(Buspirone)(Buspirone)

Indications:Indications:-adult Generalized Anxiety Disorder-adult Generalized Anxiety Disorder Pathophysiology:Pathophysiology: symptoms same as adults symptoms same as adults History:History: continuity across age span but not usually continuity across age span but not usually

manifested (dx) below age 6 yearsmanifested (dx) below age 6 years Response:Response: improvement in same clinical signs and sx used improvement in same clinical signs and sx used

for diagnosis of adultsfor diagnosis of adults Studies:Studies: (a) 2 multi center randomized double blind (a) 2 multi center randomized double blind

placebo controlled-studies to evaluate efficacy & safety-placebo controlled-studies to evaluate efficacy & safety- (b) PK open-labeled dose escalation(b) PK open-labeled dose escalation ResultsResults: safety & effectiveness not established in patients : safety & effectiveness not established in patients

6-17 years at doses recommended for use in adults-PK 6-17 years at doses recommended for use in adults-PK parameter (AUC / Cmax) of drug found to be equal to or parameter (AUC / Cmax) of drug found to be equal to or higher in children and adolescents than that in adults. higher in children and adolescents than that in adults.

Psychotropics: An ExperiencePsychotropics: An Experience(Fluvoxamine)(Fluvoxamine)

Indications:Indications: - obsessive compulsive disorder - obsessive compulsive disorder Pathophysiology:Pathophysiology: symptoms the same as adults symptoms the same as adults History:History: continuity across age span not usually dx continuity across age span not usually dx

below 6 years of agebelow 6 years of age Response:Response: Improvement in same clinical signs and Improvement in same clinical signs and

symptoms used for diagnosis of adultssymptoms used for diagnosis of adults StudiesStudies: (a) multicenter/open label PK study, : (a) multicenter/open label PK study, (b) long term open label safety study(b) long term open label safety study Results:Results: dose adjustment (increased dose) may be dose adjustment (increased dose) may be

necessary in adolescents, and girls 8-11 years of necessary in adolescents, and girls 8-11 years of age may require lower doseage may require lower dose

Antiepileptics: An ExperienceAntiepileptics: An Experience(Gabapentin)(Gabapentin)

Indication:Indication: epilepsy/partial seizures epilepsy/partial seizures Pathophysiology:Pathophysiology: clinical and symptom markers clinical and symptom markers

used for diagnosis similar for all agesused for diagnosis similar for all ages HistoryHistory - continuity across age span - continuity across age span ResponseResponse - Improvement in same clinical signs and - Improvement in same clinical signs and

symptoms as used for diagnosis of adultssymptoms as used for diagnosis of adults StudiesStudies - (a) double-blind random placebo - (a) double-blind random placebo

controlled, parallel group efficacy and safety study controlled, parallel group efficacy and safety study as add-on therapy (b) population PK, (c) open as add-on therapy (b) population PK, (c) open label extension study, (d) single dose PKlabel extension study, (d) single dose PK

Antiepileptics: An ExperienceAntiepileptics: An Experience(continued)(continued)

Results - safety and effectiveness down to 3 years Results - safety and effectiveness down to 3 years neuropsychiatric AE’s identified in 3-12 yr old; oral neuropsychiatric AE’s identified in 3-12 yr old; oral clearance (normalized by body weight) increased in clearance (normalized by body weight) increased in children < 5 yrs; higher doses required in children < 5 children < 5 yrs; higher doses required in children < 5 yrsyrs

Cardiovascular: An ExperienceCardiovascular: An Experience(Enalapril)(Enalapril)

Indication:Indication: hypertension hypertension Pathophysiology:Pathophysiology: clinical and sx markers used for clinical and sx markers used for

diagnosis for all agesdiagnosis for all ages HistoryHistory - course in prepubertals may differ from - course in prepubertals may differ from

adolescents and adultsadolescents and adults ResponseResponse - improvement in same clinical signs and - improvement in same clinical signs and

symptoms as used for the dx in adultssymptoms as used for the dx in adults StudiesStudies - (a) open label PK study -(b) double blind, dose - (a) open label PK study -(b) double blind, dose

response studyresponse study ResultsResults - Labeling for 1 mo. - 16 yrs of age, info. on dose, - Labeling for 1 mo. - 16 yrs of age, info. on dose,

efficacy and pharmacokinetics - information on efficacy and pharmacokinetics - information on preparation of a suspensionpreparation of a suspension

Cardiovascular: an experienceCardiovascular: an experience(Fosinopril)(Fosinopril)

Indication - HypertensionIndication - Hypertension Pathophysiology -Symptoms same as adultPathophysiology -Symptoms same as adult History – course in prepubertal may differ from adolescent and History – course in prepubertal may differ from adolescent and

adultsadults Responses – improvement in same clinical signs and symptoms Responses – improvement in same clinical signs and symptoms

used for the dx of adultused for the dx of adult Studies – Studies –

open label, multicenter, single dose PK study (1 mo–16 yrs) open label, multicenter, single dose PK study (1 mo–16 yrs) Multicenter, randomized, double blind dose ranging and placebo Multicenter, randomized, double blind dose ranging and placebo

controlled study (6-16 yrs)controlled study (6-16 yrs) Results – Results –

New recommended dose in children weighing more than 50 kg.New recommended dose in children weighing more than 50 kg. New information on PK parametersNew information on PK parameters An appropriate dose strength is not available for children weighing An appropriate dose strength is not available for children weighing

less than 50 kg.less than 50 kg.

The Conduct of Pediatric Studies: The Conduct of Pediatric Studies: What have We learned in the area of What have We learned in the area of Pharmacokinetic/PharmacodynamicsPharmacokinetic/Pharmacodynamics

Some examplesSome examples ProducesProduces

Some populations may need to Some populations may need to start therapy at lower end of start therapy at lower end of dosing to avoid AEdosing to avoid AE

Midazolam hydrochlorideMidazolam hydrochloride

Elimination ½ life may be Elimination ½ life may be shorter in pediatric patients shorter in pediatric patients than adultsthan adults

Atovaquone/proguanilAtovaquone/proguanil

Volume of distribution and ½ Volume of distribution and ½ life may differ in a fashion life may differ in a fashion which necessitates doses higher which necessitates doses higher in younger children than adultsin younger children than adults

EtodolacEtodolac

The Conduct of Pediatric Studies: The Conduct of Pediatric Studies: What have We learned in the area of What have We learned in the area of

Pharmacokinetic/Pharmacodynamics Pharmacokinetic/Pharmacodynamics (cont.)(cont.)

Some examples (cont.)Some examples (cont.)

Higher oral clearance by Higher oral clearance by body weight in patients < 5 body weight in patients < 5 yrs necessitated higher doseyrs necessitated higher dose

GabapentinGabapentin

Body surface area is more Body surface area is more important covariant and important covariant and more relevant than agemore relevant than age

Sotalol hydrochlorideSotalol hydrochloride

Pharmacokinetic parameters Pharmacokinetic parameters (area under the curve and (area under the curve and maximum concentration of maximum concentration of drug) may be equal to or higher drug) may be equal to or higher in children and adolescents in children and adolescents than in adults and no than in adults and no demonstrated efficacydemonstrated efficacy

Buspirone hydrochlorideBuspirone hydrochloride

What are the Gaps in What are the Gaps in Information? Information?

Many populations such as infants, neonates both Many populations such as infants, neonates both term and pre-term remain to be studiedterm and pre-term remain to be studied

Still a lot to be learned in terms of clear E-R Still a lot to be learned in terms of clear E-R relationship across the various special relationship across the various special populations.populations.

Development of appropriate pediatric Development of appropriate pediatric formulationsformulations