The extrapolation refers to establishing the PK or pharmacodynamic similarity (as defined in the answer to Q2). This will cover alternative routes of administration (e.g. SC vs. IV) or dosing regimens (flat vs bodyweight-based dosing, change in dosing interval (e.g. weekly vs monthly)) in one indication and considering them comparable across indications. 

Adequate characterization of the PK, PD and exposure-response relationship of the mAb as well as their determinants (covariates) in all the indications of interest is a prerequisite for the acceptability of extrapolation of posology, or alternative routes of administration across approved indications. Distribution of clinically relevant covariates in the model-building dataset and adequate covariate modelling across indications are considered of particular interest.

Differences in PK, PD and/or exposure-response that could preclude extrapolation of posology changes and alternative routes of administration across indications should be investigated. For example, the relevance of clinical endpoints (PFS/OS) may not be similar across indications/histologies. Moreover, because of the disease effects on PK, pharmacokinetic metrics might also vary across indications/histologies e.g. (neo)adjuvant and advanced cancer treatments.

Three different case scenarios are to be distinguished in this regard:

• Case 1: The PK exposures reached with the approved therapeutic doses/regimens in the concerned indication are known to be in the flat part of the exposure-response curve: 

In this case, for efficacy, posology changes across indications based on PK comparability should be supported by simulations that should demonstrate non-inferiority of the relevant PK parameter/metric (C_min, AUC) when compared to the corresponding metric with the approved dose regimen. 

Non-inferiority margins and relevance of the chosen PK parameter/metric should be justified by exposure-response considerations and specified in the protocol/analysis plan.

If exposure-response is characterized for efficacy, but not for safety, a description of the safety profile of the mAb in the approved posology in the concerned indication should be included and justification should be provided to support a comparable or favourable safety profile with the alternative posology in the concerned indication.

• Case 2: The PK exposures reached with the approved therapeutic doses/regimens in the concerned indication are known to be in the ascending part of the exposure-response curve

In this case, posology changes across indications based on PK comparability should be supported by simulations, that should support PK similarity of the relevant PK parameter/metrics (C_min, AUC) with the approved dosing regimen(s). The PK comparability for the alternative dosing protocol should be demonstrated for central tendency (e.g., median, geometric mean, etc.). In addition, comparability should be demonstrated for dispersion parameters (range, prediction intervals, etc.). 

The relevance of the PK parameter/metric for the efficacy and safety should be adequately justified based on exposure-response considerations. Acceptance criteria for PK comparability should be specified in the protocol/analysis plan.

Longitudinal PK/pharmacodynamic (target engagement, tumor size other biomarkers) modelling could be useful in providing supporting information that the changes in PK profile are not associated with changes in the benefit-risk profile of the mAb in the concerned indication.

If exposure-response is characterized for efficacy, but not for safety, a description of the safety profile of the mAb in the approved posology in the concerned indication should be included and justification should be provided to support a comparable or favourable safety profile with the alternative posology in the concerned indication.

• Case 3: The exposure-response is not characterised in the concerned indication

Posology changes cannot be extrapolated across indications without understanding of the exposure response relationship.

Non-inferiority to the approved dose regimen should be demonstrated for drug activity such as ORR as primary endpoint, with similarity/non-inferiority of relevant PK parameters as secondary endpoints. Acceptance criteria for PK similarity/non-inferiority should be specified in the study protocol.

If exposure-response is not characterized for safety, a description of the safety profile of the approved posology in the concerned indication should be provided to support a comparable or favourable safety profile of the mAb in the alternative posology in the concerned indication.