August 5, 2013

Written by Dr. Paolo Biffignandi, Advisory Board member of the pan-European pharmaceutical regulatory affairs organisation ELC Group and former President of TOPRA (The Organisation for Professionals in Regulatory Affairs).

The European Medicines Agency (EMA) announced on 31 January 2013 that it had released a draft guideline to revise the agency’s current guideline on biosimilars containing low molecular weight heparins (LMWHs), a type of medical product often used in surgical settings as an anticoagulant and incorporated into a wide range of products. The draft guideline was released for a six-month public consultation period (

LMWHs are prepared from unfractionated heparin by various chemical or enzymatic depolymerisation processes. Thus, the starting material of LMWHs is of biological origin (mainly from porcine intestinal mucosa) and the manufacturing process defines the characteristics of the drug substance. LMWHs are used as anticoagulants for the treatment of thrombotic and cardiovascular disorders. The complexity of LMWHs results largely from the nature of the starting material, the extraction, the fractionation and the production processes.

The proposed guideline lays down the non-clinical and clinical requirements for biosimilars containing LMWHs and claiming to be similar to a LMWH that is already marketed. The revised guideline would replace the current guideline (EMEA/CHMP/BMWP/118264/2007), which came into effect in October 2009.

The non-clinical section of the previous guideline has been revised to reflect that a risk-based approach can be followed. In vivo studies will not be required as part of the comparability exercise if physicochemical and biological characterisation of the biosimilar and the reference LMWH has been performed with a high level of resolution and have convincingly demonstrated close similarity. Otherwise, in vivo models are required and should include either an appropriate pharmacodynamics model or a suitable animal venous or arterial thrombosis model. From a toxicological standpoint, the EMA said it will generally not require separate repeated dose toxicity studies, but the need for such studies in specific cases such as the introduction of novel excipients should be assessed on a case-by-case basis.

Clinical studies represent something of a challenge to sponsors, the EMA explained: ‘Due to the heterogeneity of LMWHs, conventional pharmacokinetic studies cannot be performed. Instead, the absorption and elimination characteristics of LMWHs should be compared by determining pharmacodynamic activities (including anti FXa and anti-FIIa), as surrogate markers for their circulating concentrations.”

The clinical section of the previous guideline has been revised to reflect the fact that a dedicated efficacy study may now ‘be waived in exceptional situations’. The revised guideline states that biosimilars manufacturers would not have to conduct trials to show comparable efficacy to a reference product if similar efficacy can be ‘convincingly deduced’ from comparison of physiochemical characteristics, biological activity and potency and pharmacodynamic fingerprint profiles. The guideline does mention, however, that this scenario would be the exception to the rule, as the amount of ‘reassurance from analytical data and bioassays would be considerable’. Most sponsors, then, will need to conduct a clinical trial in which they focus on therapeutic equivalence of the two products. The most sensitive trials model used to show equivalency would include surgical patients — and especially those undergoing major orthopaedic surgery — who have a high risk of developing venous thromboembolisms (VTEs), more commonly known as blood clots. VTEs can cause serious and fatal adverse events if they break free, so any differences between the similar biological product and the reference product could cause clinically significant differences as well.

Safety data will also be required, and regulators said that sponsors should compare the type, frequency and severity of any adverse events occurring in the studied patients. Sufficient reassurance should also be provided that the biosimilar is not associated with excessive immunogenicity compared with the reference product.

Dr. Paolo Biffignandi,

August 5, 2013

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