model is applicable would be very helpful in this context. E.g., which aspects need to be considered? Which conditions must be met and what defeats an application of these models? 172-173 Comment: The so-called Extrapolation concept and Extrapolation plan are formal documents that need to be developed prospectively by the applicant and be approved by the Agency to initiation of the programme. It follows that any prospective data-driven modelling activity that is not included in the plan cannot be performed unless the plan is amended. Such a regulatory strategy amounts to a duplication of the PIP efforts and to a further leap in the administrative burden, a loss of agility and potential additional delays in the overall clinical development programme. Also, in all circumstances, the agency consider that the applicant should bring forward the evidence supporting the extrapolation concept for any disease and target population, instead of the agency determining beforehand whether such extrapolation is generally endorsed. The burden of evidence gathering is thus transferred to all applicants individually and this is not an efficient process. The agency may wish to suggest an overall strategy of extrapolation concept, extrapolation plan, mitigation plan etc, but should not impose mandatory review and approval at each step of the procedure which is of doubtful/questionable added value while tremendously increasing the delays and administrative costs. The obvious exception is when the extrapolation concepts are included in a PIP (which is to be approved and amended according to existing processes, which are already formal and 174-176 Comment: “It is important to seek regulatory agreement on an extrapolation concept and proposed extrapolation plan before studies are conducted, and again for important
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.
helpful if methods for validation could be expanded. The pathway for a “failed” extrapolation concept needs to be further detailed. 438-440 Comment: The title of 5.2.2 includes "validation" but this first sentence implies updating the model with the new paediatric data. Lines 442 and 443 Comment: The phrase "the extrapolation concept needs to be updated (see section 5.2)" does not make sense in context. Section 5.2 is the extrapolation plan, not the extrapolation concept. Furthermore, “(see section 5.2)” is inconsistent with how sections have been referred to earlier in the document (see comments above regarding lines 295, 300, and 304). Consider correcting the cross references. Proposed change (if any): "the extrapolation concept plan needs to be updated (see section 5.2, Extrapolation plan)". Section 5.3 448-450 Comment: We suggest the term “minimize” risks instead of “mitigate” Proposed change (if any): A formal, structured plan to mitigate minimize risks and address key uncertainties during development and in the post-authorisation setting should be proposed as part of the extrapolation plan and updated in response to the results of the studies conducted. 452 Comment: We suspect that the word “population” is missing and the end of the first sentence Proposed change (if any): “… being generated in the target population.” 454-455 Comment: