children if they may be exposed to doses that a priori are not expected to maximize benefit based on what is known from the adult source. Measures to handle…” 340-341 Comment: PK of monoclonal antibodies tends to be similar in adults and children. In this situation, modelling and simulation may be acceptable in determining starting doses. Proposed change: Replacement of PK studies with modelling and simulation may be appropriate in certain circumstances but in general PK studies should be required. Suggest modifying sentence since there may be situations other than paediatrics where there may NOT be gaps in PK/PD. Comment: Are there any examples of where PK or PKPD studies for dose selection purposes can be replaced? In addition, it be possible to define what these youngest age groups would be? Is it 1 month or 2 years etc. Proposed change (if any): Clarify when it may be acceptable to replace PK or PKPD studies with model predictions. 341-344 Comment: Extrinsic factor that can affect the predictions should be considered. Proposed change (if any): For example, gaps in knowledge of intrinsic factors related to maturation, ontogeny of enzymatic and transport functions or pharmacogenetics and also to extrinsic factors (e.g. diet, geographic), particularly in the youngest age groups of the paediatric population are sources of uncertainties and can affect the reliability in the predictions.
children if they may be exposed to doses that a priori are not expected to maximize benefit based on what is known from the adult source. Measures to handle…” 340-341 Comment: PK of monoclonal antibodies tends to be similar in adults and children. In this situation, modelling and simulation may be acceptable in determining starting doses. Proposed change: Replacement of PK studies with modelling and simulation may be appropriate in certain circumstances but in general PK studies should be required. Suggest modifying sentence since there may be situations other than paediatrics where there may NOT be gaps in PK/PD. Comment: Are there any examples of where PK or PKPD studies for dose selection purposes can be replaced? In addition, it be possible to define what these youngest age groups would be? Is it 1 month or 2 years etc. Proposed change (if any): Clarify when it may be acceptable to replace PK or PKPD studies with model predictions. 341-344 Comment: Extrinsic factor that can affect the predictions should be considered. Proposed change (if any): For example, gaps in knowledge of intrinsic factors related to maturation, ontogeny of enzymatic and transport functions or pharmacogenetics and also to extrinsic factors (e.g. diet, geographic), particularly in the youngest age groups of the paediatric population are sources of uncertainties and can affect the reliability in the predictions.
efpia-comments_extrapolation-rp_final-22jan2018.docx