FIGURE 2
Step-wise approach to biosimilar development ( adapted from 3 )
Step 1 Step 2
Step 3
Comparative clinical studies Pharmacokinetic / pharmacodynamic Efficacy + safety + immunogenicity
Comparative non-clinical studies Pharmacodynamic Toxicology
Comparative quality studies Analytical : physical + chemical properties Functional : biological / pharmacological activity
analytical based assessment that focuses on demonstrating the biosimilar ’ s comparative similarity to the reference product without any clinically meaningful differences . Comparability assessment is a stepwise process for each biosimilar product with knowledge gained from the comparative quality studies , used to determine the extent and type of non-clinical and clinical studies ( see Figure 2 ).
Comparability studies are a known concept following changes in the manufacturing process of biologics . Comprehensive physicochemical and functional in vitro studies must be performed and approved by the regulators when there are significant changes from the manufacturing process but which are not expected to affect either safety or efficacy . For instance , approval of a biosimilar requires comprehensive comparative quality studies to prove that the physicochemical properties and biological activity are highly similar to the RP . 2 Due to the natural variability of the biological source and the unique manufacturing process , minor differences will occur between the biosimilar and its RP . 2 Minor variability is only permitted when the scientific evidence demonstrates that these changes do not affect the safety , efficacy and immunogenicity of the biosimilar . The range of variability allowed for a biosimilar is the same as that allowed between batches of its RP . The product attributes that are critical to the safety , efficacy , and potency of the product are classified as critical quality attributes ( CQAs ). 4 Those that can be assessed by orthogonal analytical methods are primary structure , higher order structure , glycosylation pattern , product related variants ( aggregates , fragments , charge variants ) and process-related variants ( host cell proteins , host cell DNA , other impurities ). 4
Comparative non-clinical studies are usually done in cell cultures to show binding , activation or inhibition of physiological targets and thereby demonstrating functional similarity .
Clinical trials Clinical trials are needed to confirm that the clinical performance of biosimilars is comparable to the reference product . Trials are undertaken in healthy volunteers or patients to detect product-related differences that could affect the pharmacokinetics ( PK ) or pharmacodynamics ( PD ). Efficacy can be measured as pharmacodynamic activity when the PD endpoint correlates with clinical benefit . Examples include a glucose clamp study for biosimilar insulins , absolute neutrophil count for biosimilar granulocyte-colony stimulating factor and the number of oocytes retrieved for folliclestimulating hormone . 2 If no suitable PD endpoints are available , a clinical trial in a representative patient population and sensitive indication is needed to confirm efficacy . For monoclonal antibodies and other complex molecules , a comparative clinical study with a conventional clinical efficacy endpoint is required . When designing the randomised , parallel-group studies , adequate equivalence margins should be chosen for the primary efficacy endpoint . Adequacy of the range is given when differences have no clinical relevance .
The amount of safety data collected depends on the type and severity of safety concerns with the RP or pharmacological class and is should be examined throughout the clinical studies .
Testing of potential immunogenicity in clinical studies is obligatory in the case of biotechnology-derived medicines ( RPs and biosimilars ). 2
Immunogenicity Immunogenicity is the inherent potential for a therapeutic protein product to generate an unwanted immune response to itself or to related proteins and causing adverse immunological reactions . 5 This occurs when the patient develops anti-drug antibodies ( ADAs ) which bind to the biologic product , reduce efficacy ( neutralising ADAs ) or elicit hypersensitivity reactions such as anaphylaxis . Severe immune reactions may result from the cross-reaction of ADAs with an endogenous protein and the subsequent loss of function . Immune reactions depend on product-related factors ( e . g ., changes of the protein during transport and storage , especially aggregate formation ), process related factors ( subcutaneous versus intravenous administration , short-term versus chronic administration ) and patient-related factors ( type of disease , immune status , genetic status , concomitant treatment ). Immunogenicity data are required for approval of any biological medicine , 2 , 5 because animal studies are of limited value in predicting immune response in humans . Clinical studies on immunogenicity should look at both short-term immune responses ( infusion-related reactions ) and longer-term reactions ( incidence , titre , persistence , and neutralising activity of ADAs ). As rare immune reactions can only be detected after a long follow-up period in larger numbers of patients , immunogenicity monitoring is a key issue of post-marketing surveillance and pharmacovigilance .
Extrapolation If a biosimilar shows a highly similar safety and efficacy in one therapeutic indication , safety and efficacy may be extrapolated to other indications authorised for the RP . This avoids unnecessary repetition of clinical trials already carried out with the RP . 2
The criteria for extrapolation are carefully checked by the regulators and include :
• the mechanism of action must be mediated by the same receptor ( s ) for the indication tested in patient studies and the extrapolated indication
• the study population of the indication tested must be sensitive enough to detect potential differences in clinical performance
• the applicability of comparable safety and efficacy in different therapeutic areas must be given
• a comparable safety profile of the biosimilar and the
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