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44 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 P h a r mTe c h . c o m Extrapolation based on efficacy Pediatric exposure-response (E-R) relationship data are often lacking when the pediatric investigation plan (PIP) for the initial indication is proposed. This, in general, may result in having to perform a dose-ranging study in chil- dren prior to the pediatric Phase III study. In addition, having a placebo control arm in a pediatric efficacy and safety study with chronic dosing up to one year is not only operationally challenging due to patient enrollment and retention in the study, but also is considered unethical and not recommended by current legislation (10, 11). However, for benefit/risk assessment purposes, having a proper con- trol in the pivotal study is generally required by the regu- latory agency in order to demonstrate efficacy and safety. An example of an immunoglobulin G1 (IgG1) mono- clonal antibody (mAb) against two distinct specific cell surface targets expressed on leukocytes in the indication of inf lammatory disease was aimed to leverage pediatric E-R data from literature or real-world data (RWD) of similar classes of biologic therapies to support dose extrapolation from the adult program. Given the similarity in disease and in drug response between pediatrics (age ≥4 years) and adults are well established, the effort focused on leverag- ing the adult data to support a pediatric Phase III design with either a virtual placebo or no placebo arm during the long-term maintenance phase. This example demonstrates a successful outcome supported by both FDA and EMA in finding a compromise that allows implementation of extrapolation of efficacy using adult data to support the elimination of an extensive dose-ranging trial in children and the possibility of using a virtual placebo or no placebo arm in the proposed pediatric Phase III study. The key elements of extrapolation of efficacy approach are as follows: • A typical Phase II dose-ranging study was to be re- placed by the collection of pharmacokinetic (PK)/ pharmacodynamics (PD) and dose-ranging informa- tion from a small Phase I PK/PD pediatric study in- volving a minimum of 12 subjects. The dose-ranging element would also be directly incorporated into the Phase III study. • A small, unpowered Phase III study was proposed in the EMA PIP to collect both dose-ranging informa- tion and clinical evidence demonstrating a favorable benefit/risk profile. The primary and secondary effi- cacy endpoints were to be evaluated descriptively with point estimates (e.g., proportion of patients) and corresponding 95% confidence intervals. • The selection of dose regimens for the Phase III dose-ranging phase would be supported by a model- ing and simulation approach after obtaining PK/PD information from the Phase I pediatric study, aiming to match the exposure between pediatric and adult patients (Dose #1), as well as based on the adult Phase III E-R relationship analysis results to help identify a second dose for dose ranging evaluation in the pediatric Phase III study (Figure 2). • Extrapolating efficacy from adult patients by bench- marking the pediatric efficacy to that of adult data allows the size of the placebo control in the pediatric Phase III study to be reduced. As a result of implementing an overall extrapolation ap- proach, the final study sample size was reduced by more than 50% and the overall pediatric development timeline shortened by 12–18 months, hence potentially accelerat- ing the approval of the IgG1 mAb for pediatric patients (Figure 2). Although minimizing a placebo control arm in the Phase III study may not be generalized across different 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 ref lects an application of extrapolation based on the principle of similar exposure in pediatrics and adults will result in similar efficacy. In this case study, pedi- atric dose selection included conversion from body surface area to weight-based dosing, and dose recommendation for a new formulation and a new indication. Quality Collaboration Figure 1. Scope of the IQ CPLG Pediatric Working Group with respect to pediatric extrapolation. ALL FIGURES ARE COURTESY OF THE AUTHORS. For benefit/risk assessment purposes, having a proper control in the pivotal study is generally required by the regulatory agency in order to demonstrate efficacy and safety.