Issue link: https://www.e-digitaleditions.com/i/1354372
32 BioPharm International eBook March 2021 www.biopharminternational.com sever al workshops and webinar s to inform relevant stakeholders and interested parties (5–7). The PWG has also published on related topics to describe the chal- lenges and successful applications of pediatric extrapolation (8, 9). This paper highlights t wo case studies describing pediatric medi- cines development programs using a pediatric extrapolation frame- work, endorsed by the European Medicines Agency (EMA) and/or FDA. These case studies demon- strate the application of model-in- formed quantitative approaches to integrate prior knowledge of the disease and available data within and/or across indications to sup- port selection of dose and regimen for pediatric Phase II/III studies. This extrapolation framework has also been successful in waiving the need for a placebo control arm in pediatric Phase III studies, and in supporting pediatric formulation qualification and labeling claims. EXTRAPOLATION BASED ON EFFICACY Pediatric exposure-response (E-R) relationship data are often lacking when the pediatric investigation plan (PIP) for the initial indica- tion is proposed. This, in general, may result in having to perform a dose-ranging study in children prior to the pediatric Phase III study. In addition, having a placebo con- trol arm in a pediatric efficacy and safety study with chronic dosing up to one year is not only operationally challenging due to patient enroll- ment and retention in the study, but also is considered unethical and not recommended by current legis- lation (10, 11). However, for benefit/ risk assessment purposes, having a proper control in the pivotal study is generally required by the regula- tory agency in order to demonstrate efficacy and safety. A n e xa mple of a n i m mu no - globulin G1 (IgG1) monoclonal antibody (mAb) against two dis- tinct specific cell surface targets expressed on leukocy tes in the indication of inflammatory 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 pro- gram. Given the similarity in dis- ease and in drug response between pediatrics (age ≥4 years) and adults are well established, the effor t focused on leveraging the adult data to support a pediatric Phase III design with either a virtual pla- cebo 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 compro- mise that allows implementation of extrapolation of efficacy using adult data to support the elimina- tion of an extensive dose-ranging trial in children and the possibility of using a virtual placebo or no placebo arm in the proposed pedi- atric Phase III study. The key elements of extrapolation of efficacy approach are as follows: • A typical Phase II dose-ranging study was to be replaced by the collection of pharmacoki- netic (PK)/pharmacodynamics (PD) and dose-ranging infor- mation from a small Phase I PK/PD pediatric study involv- ing a minimum of 12 subjects. T he dos e -r a ng i ng e le me nt would also be directly incorpo- rated into the Phase III study. • A sma l l, u npowered Phase I I I st udy wa s prop ose d i n the EMA PIP to collect both d o s e - r a n g i n g i n fo r m at io n and clinical evidence demon- strating a favorable benefit/ risk profile. The primary and secondary efficacy endpoints were to be evaluated descrip- tively w ith point estimates (e.g., proportion of patients) and corresponding 95% confi- dence intervals. • The selection of dose regimens for the Phase III dose-rang- ing phase would be supported by a modeling and simula- tion approach after obtaining PK/PD information from the Phase I pediatric study, aim- ing to match the exposure between pediatric and adult pat ients ( Dose #1), as well as based on the adult Phase I I I E -R relat ionsh ip a na ly- sis results to help identify a second dose for dose ranging evaluation in the pediatr ic Phase III study (Figure 1). • Extrapolating efficacy from adult patients by benchmark- ing 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 approach, the final study sample size was reduced by more than 50% and t he overa l l p e d iat r ic develop - Regulatory Sourcebook Quality Collaboration 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.