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34 BioPharm International eBook March 2021 www.biopharminternational.com ment timeline shortened by 12–18 months, hence potentially accel- erating the approval of the IgG1 mAb for pediatric patients (Figure 1). Although minimizing a placebo control arm in the Phase III study may not be generalized across dif- ferent indications or drug classes, such an approach could signifi- cantly improve the feasibility and delivery of the study and enables a more patient-centric trial design. EXTRAPOLATION BASED ON SIMILAR EXPOSURE A second example reflects an appli- cation of extrapolation based on the principle of similar exposure in pediatrics and adults will result in similar efficacy. In this case study, pediatric dose selection included conversion from body surface area to weight-based dosing, and dose recommendation for a new formu- lation and a new indication. Dasatinib is a small molecule, BCR-ABL tyrosine kinase inhibi- tor (TKI) approved in adults and pediatrics for treating Philadelphia c h r o m o s o m e - p o s i t i v e ( P h + ) c h r on ic mye loid le u ke m i a i n chronic phase (CML-CP) and Ph+ ac ute ly mphobla st ic le u ke m ia (ALL). Dasatinib daily oral doses in adults are 100 mg for CML-CP and 140 mg for advanced phases CML and ALL. Dosing for children (1 year of age and older) and adoles- cents is based on body-weight tier. Dasatinib is administered orally once daily as film-coated tablets or powder for oral suspension in pediatrics subjects. The dasatinib pediatric devel- opment prog ram was based on extrapolation principles of dis- ease similarit y and response to treatment in Philadelphia chro- mosome positive (Ph+) CML - CP and ALL between adult and pedi- atric patients of all age groups. It supports extrapolation of adult efficacy data in the proposed indi- cation by not requiring a f ully powered confirmatory Phase III trial in pediatrics. In the Phase I st udy, no m a x i mu m-tole r ate d dose (MTD) was identified with b o d y s u r f ac e a r e a - b a s e d d o s - ing at 60, 80, 100, and 120 mg/ m 2 once daily. Dasatinib exposure from 60 mg/m 2 in pediatric sub- jects was comparable to 100 mg in adults and served as the tar- get exposure for weight-tier dose recommendations and develop - ment of an age-appropriate formu- lation for pediatric patients (12, 13). The integrated PB/PK model was developed to elucidate the absorption mechanism and role of various factors such as phys- icochemical properties, absorp - tion characteristics, and inherent differences in dosage form transit behavior related to dasatinib bio- equivalence. In the absence of the observed PK data in ALL pediatric patients, simulations based on the PB/PK model were used to extrapo- late PK from monotherapy in CML patients to the dasatinib-chemo combination in ALL patients and further justify body weight-based dosing recommendations for the new formulation (14). In summary, extrapolation sup- ported the successful approval of a pediatric indication for dasatinib and informed dosing and posology. IMPACT OF DATA EXTRAPOLATION While pediatric legislation in the United States and Europe has led to accelerated growth in the num- ber of med ic ines approved for use in children, a lengthy delay between initial adult authoriza- tion and the addition of pediatric labeling remains, approximately seven years on average (15). The case studies described here demon- strate the practical utility of the pediatric extrapolation framework to advance and expedite pediatric drug development. Regulatory Sourcebook Quality Collaboration Figure 1. Shift from a pediatric development program employing multiple pharmacokinetic (PK)/pharmacodynamics (PD) trials followed by full placebo- controlled Phase III (top box) to a single small PK/PD study followed by a smaller Phase III with virtual placebo (bottom box) by means of extrapolation. IND is induction, MNT is maintenance, LD is low dose, HD is high dose, OLE is open label extension. Age groups: 4 to <12 years, 12 to <18 years. FIGURE COURTESY OF THE AUTHORS.