WHO guideline for abbreviated licensing pathways for certain biological therapeutic products - Clinical evaluation - Martina Weise, MD Federal Institute for Drugs and Medical Devices, Germany
General considerations Main studies: use final formulation derived from final manufacturing process (otherwise justification and/or adequate additional data needed) Reference product necessary for comparison (Non)Clinical data requirement depends on - Extent of possible characterisation - Observed / potential differences - Clinical experience with substance class
Pharmacology Studies Biosimilar Obligatory comparative Usually single dose PK/PD Sensitive test system to detect potential differences Absorption and elimination Predefine equivalence criteria Investigate all routes of administration applied for Usually no other pharmacology studies Clinical comparability Preferably comparative (design see biosimilar) Similar PK /PD profiles (+potency) may justify omission of dose-finding studies Omission of other pharmacology studies (e.g. interaction studies, special population) only if appropriately justified
Efficacy Studies Biosimilar No dose-finding studies Confirmatory, randomized, (double)blind equivalence trials (ICH E9 and E10) Sensitive and wellestablished test model Demonstration of equivalent efficacy Equivalence margins appropriately justified Clinical comparability Omission of dose-finding studies to be justified Comparative, randomized, (double)blind, confirmatory trials (ICH E9 and E10) Study population = target population applied for Demonstration of noninferior/equivalent efficacy Non-inferiority/equivalence margins to be justified
Confirmatory PK/PD Studies Comparative PK/PD studies may suffice if PD marker(s) accepted surrogate marker(s) for efficacy Relationship PK-PD-clinical effect known Equivalence margin appropriately justified Dose(s) within the linear part of the dose-response curve
Safety Pre-licensing data amount should be sufficient to characterize safety profile Comparison (with reference product) of type, frequency, severity of AEs Data from pre-authorisation studies usually too limited to identify all ADRs Pharmacovigilance Plan
Immunogenicity Comparative human data (animal data usually not predictive) Optimal antibody testing strategy (e.g. periodicity and timing of sampling, interference with antigen) Sensitive validated screening assay, further characterisation of antibodies (e.g. neutralising capacity) Potential clinical implications of identified antibodies Chronic administration usually one-year data pre-licensing to assess antibody incidence, persistence, titres over time etc.
Extrapolation Biosimilar Extrapolation to other indications of the reference product possible if Similarity in all aspects (quality + safety + efficacy) Demonstrated in sensitive test system(s) Same mechanism of action and/or involved receptor Safety and immunogenicity sufficiently characterized Clinical comparability No extrapolation to other indications (not studied during development) Demonstration of convincing similarity in all characteristics not possible Non-inferiority does not exclude superior efficacy Extrapolation to indications with different posology difficult to justify
Pharmacovigilance Pharmacovigilance Plan (ICH E2E) To be submitted at the time of MAA Safety specification (identified and potential safety issues) Planned post-marketing activities and methods Risk minimisation measures (e.g. educational material) Specific safety monitoring imposed on reference product or product class to be taken into account Competent authorities should assess PhV plan, PhV system and monitor compliance of MAH