About this guideline
Adopted by the TGA: 08 June 2023
Overseas effective date: 1 June 2017
Replaces: EMEA/CHMP/BMWP/118264/2007
Categories: Multidisciplinary | Biosimilar
TGA annotations:
Section 4: Specific aspects of the quality comparison
To demonstrate sufficient similarity and sameness in structure and function, the sponsor should analyse as many batches of the reference and biosimilar medicines as possible to allow meaningful quantitative ranges to be established. The criteria for acceptance are that the enoxaparin biosimilar data should fall completely WITHIN the ranges of the reference medicine analyses for the following characteristics:
- molecular weight distribution and overall chemical composition
- starting material (tissue type and species) and mode of depolymerisation
- disaccharide building blocks, fragment mapping profiles and sequences of selected unfragmented oligosaccharides
- biological and biochemical assays.
The physicochemical analyses must unequivocally demonstrate that the sequence and structure of enoxaparin are identical between the reference medicine and the biosimilar.
Failure to meet these criteria may result in rejection or withdrawal of the biosimilar submission.
Section 5: Non-clinical studies
Pharmacodynamic studies
In vivo studies
- In vivo pharmacodynamic studies are not required provided the physicochemical and in vitro characterisation demonstrates the biosimilar is fully biosimilar to the reference product.
Toxicological studies
- The EMA guideline states that “consideration should be given to investigating the ability of the HPF4 complexes to bind to previously formed antibodies against HPF4 and to activate thrombocytes by using sera from HIT II patients.” Such a study would be expected to be submitted in Module 4, noting that the antibodies used in such an assay should not be monoclonal antibodies.
- Although the EMA guideline states that the “predictivity of animal studies for evaluation of immunogenicity in humans is usually considered low”, such a study may provide an indication if a difference in immunogenicity exists between the biosimilar and the reference product.
- In vitro studies comparing the immunomodulatory activity of the biosimilar with the reference product should be performed. The validity, specificity, sensitivity and conduct of the assays, as well as the analysis of the results, should be fully scientifically justified.
Section 6: Clinical studies
Pharmacokinetic/pharmacodynamic studies
The choice of pharmacodynamic endpoints in the pharmacodynamic study should be justified. The justification should include a rationale for the extrapolation of the findings of the study to clinical efficacy and safety outcomes. Equivalence margins should be pre-specified, with justified confined limits to demonstrate the test and reference LMWHs are highly similar.
- Where EU guidelines adopted in Australia include references to EU legislation (including EC Directives and Regulations), the requirements contained in the referenced EU legislation are not applicable to the evaluation of medicines by the TGA.
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For more information see International scientific guidelines adopted in Australia.