FDA Case Studies

Pediatric Oncology Subcommittee

March 4, 2003

Case 1

Dosing and Proof of Concept Submitted

Pediatric and Adult Disease are the Same

Case 1

• Types of studies: Two Phase I dose-finding studies in children with hematologic malignancies– from supplemental (S) NDA and from

original (O) NDA

• Size of data set: – for efficacy/safety: 39 [31(S) + 8(O) ]– for PK: 33 [27(S) + 6 (O) ]

Type of Information Submitted

• Safety

• PK

• PK-PD

• Proof of concept

Case 1

Results• Safety: similar to adults; MTD not reached• PK: parameters similar to adult values• PK-PD relationship: no correlation• Proof of concept

– remissions induced in the same malignancy in pediatrics as in adults, although in a limited number of pediatric patients

– remissions occurred in approximately the same proportion as in adults

Case 1

Comparison between Children & Adults

• Same side effects as adults but lower grade• Lack of PK-PD relationship

– exposure (area under the concentration-time curve) and Day 28 white blood cell count

• Lack of clear dose-proportionality– starting dose chosen to provide similar exposure

to adult doses – lack of relationship between dose and exposure

• overlap between AUCs for different doses

Case 1

Case 1. Overlap of Dose and Area under the Curve

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0.2

0.4

0.6

0.8

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1.2

1.4

1.6

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Ped Dose 1 Ped Dose 2 Adult Dose

Dose

AU

CCase 1

Issues & Conclusions

• Efficacy and extrapolation– first time extrapolation has been used for

approval

• Challenge in finding a pediatric dosage

Case 1

Case 2

Dosing Submitted

Pediatric and Adult Disease are the Same

Case 2

• Type of study: Single Phase II pharmacokinetic study in malignant and non-malignant life-threatening conditions

• Size of data set: – 24 patients– ages 5 months to 16 years

Type of Information Submitted

• Safety– Clinical Adverse Events and laboratory

abnormalities

• PK/PD– Multiple sampling in each patient with initial

dosing based on body weight and subsequent adjustment based on PK/PD information

Case 2

Results

• Safety: generally similar to adults

• PK/PD: Suggested pediatric dosing based on population PK– Two-step dosing based on body weight– < 12 kg and > 12 kg

Case 2

Comparison between Children & Adults

• Pediatric data indicate need for higher dosage in smaller children (by weight)

Case 2

Issues & Conclusions

• Limited safety information and dosing recommendations added to Special Populations - Pediatric section

Case 2

Case 3

Dosing and Proof of Concept Submitted

Preliminary Activity in a Disease found only in Pediatric Patients with the

Approved Indications for Diseases found only in Adults

Case 3

• Types of studies: – Phase I dose-finding study in children with

solid tumors and hematologic malignancies– Phase II open label single arm study for

response rate in children with refractory or relapsed solid tumors

• Size of data set: – Phase I: 48 (30 solid tumor + 18 leukemia),

ages 1-15 years– Phase II: 108, ages <1 to 15 years

Type of Information Submitted

• Safety

• PK

• PK-PD

• Proof of concept

Case 3

Results• Safety: similar to adults; MTD not reached for

leukemia, MTD for solid tumors higher than approved adult dose

• PK: parameters similar to adult values• PK-PD relationship: no relationship between

exposure and nadir white blood cell count due to maximal suppression at lowest dose

• Proof of concept – Consistent tumor responses seen in one class of

solid tumors

Case 3

Comparison between Children & Adults

• Higher doses tolerated in children

• Responses seen in some pediatric malignancies that are not found in adults

Case 3

Issues & Conclusions• The disease where activity was demonstrated in

children is a pediatric disease that is rarely found in adults

• The approved indications are diseases found almost exclusively in adults

• Extrapolation of efficacy cannot be used• Product labeling did not include the submitted

pediatric data• Product currently not approved for use in children

Case 3

Case 4

Dosing and Response Submitted

Lack of Activity

Case 4• Types of studies: Phase I dose-finding trial

in solid tumors and hematologic malignancies

• Size of data set:– Solid tumors: 25 evaluable patients– Hematologic malignancies: 4 evaluable patients– Additional 17 patients treated; inevaluable– Ages 2-17

Case 4• Types of studies: Phase II stratified open-

label study in solid tumors– Primary endpoint: Response rate

• Size of data set:– Designed to enroll at least 14 patients per subset

– CNS tumors 21 patients

– Soft tissue sarcoma 21 patients

– Neuroblastoma 4 patients

– Age < 21 (2 older ineligible pts excluded)

Type of Information Submitted

• Safety– Collected only AEs attributed to drug by PI– Post-marketing pediatric safety reports

• PK/PD– Abbreviated study reports (no primary

data)

• Efficacy– Abbreviated clinical trial study reports

Case 4

Results

• Safety: similar to adults• PK: MTD, recommended Phase II dose

identified• PK/PD: Recommended Phase II dose too

toxic; dose lowered• Efficacy

– RR 0 in CNS, neuroblastoma strata– Neuroblastoma arm closed early– 1 CR and 1 PR in soft tissue sarcoma

Case 4

Comparison between Children & Adults

• Toxicity profile similar in adults and children

• Recommended dose (after testing in Phase II) similar to that approved in adults

Case 4

Issues & Conclusions

• Brief description of study included in the label

• Negative efficacy data included in the label

• No PK or dosing data included

Case 4

Case 5

Dosing and Efficacy Submitted

Spectrum of Diseases Including Approved Adult Indication

Case 5• Types of studies:

– two Phase I studies included pharmacokinetics and dose determination data on patients with relapsed or refractory CNS & solid tumors

– one single-arm Phase II study to evaluate efficacy in relapsed or refractory CNS & solid tumors

• Size of data set:– Phase I studies: 82 patients, ages 3 to 17; 19

patients had pharmacokinetic data

– Phase II study: 122 patients, ages 3 to 17

Type of Information Submitted

• Safety

• PK/PD– multiple sampling in each patient with

initial dosing based on body surface area

• Efficacy

Case 5

Results

• Safety: similar to adults

• PK/PD– the pharmacokinetics of the drug are similar

independent of previous treatment– no relationship between age and clearance

• Efficacy: Of 122 patients, 1 CR and 5 PR

Case 5

Comparison between Children & Adults

• Similar clearance and volume of distribution values

• Response to therapy is different (worse in children)

• Responses occurred in a different histological subtype from the adult tumor

Case 5

Issues & Conclusions

• This drug was approved for an adult disease that also exists in children, BUT did not show efficacy in that disease

• Responses were seen in a disease that occurs primarily in children and for which there is available effective therapy

• What information, if any, should be included in the labeling?

Case 5

Case SummariesTypes ofStudies

InformationSubmitted

Results Comparison Issues

Case 1

Samediseaseadults &children

Phase I x 2

Total pts.-39

Safety, PK,PK/PD, Proofof Concept

Safety,dosing, andresponse torx same asadults

Drug bettertolerated inchildren, nodoseproportionality

Extrapolationused tosupportefficacy,Properpediatric dosestillindeterminate

Case 2

Samediseaseadults &children plusadditionalpediatricdiseases

Phase II

Total pts-24

SafetyPK/PD

Dosingdependentupon bodyweight withchange at 12kg

Higherpediatric dosein smallerchildren

Limited safetyand dosinginformationincluded inPediatricsSubsection ofPrecautions

Case 3

Different adultand pediatricdiseases

Phase I x 2Phase II

Total pts- 156

Safety, PK,PK/PD, Proofof Concept

Safety similarto adults,dosing higherin children, nodoseproportionality,Evidence ofactivity in apediatricdisease

Higher dosestolerated inchildren,

Extrapolationnotapplicable,Noinformation inpackageinsert

Case 4

Different adultand pediatricdiseases

Phase IPhase II

Total pts-71

Safety,PK/PD,Efficacy

Safety anddosing similarto adults, lowactivity

Safety anddosing similarto adults

Lack ofactivitydescribed inpackageinsert, nodosingprovided

Case 5

Spectrum ofpediatricdiseasesincludingapprovedadultindication

Phase I x 2Phase II

Total pts-204

Safety,PK/PD,Efficacy

Safety anddosing similarto adults, noresponses inchildren withdiseaseapproved inadults, activityin a pediatricdisease

Safety anddosing similarto adults, noactivity inapprovedindication foradults

Extrapolationnot possible