The European Medicines Agency (EMA) has released a draft scientific guideline on the development of biosimilar low-molecular-weight heparins, a type of medical product often used in surgical settings as an anticoagulant and incorporated into a wide range of products.
The guideline specifically pertains to two types of heparin: low molecular mass heparins (LMMH) and low molecular weight heparins (LMWH), both typically sourced from the intestinal mucosa of pigs.
EMA explains that sponsors will be expected to conduct both non-clinical and clinical studies to show similarity between the two products.
Non-clinical studies will include pharmacodynamics studies (in vivo and in vitro) to show similarity when measured, at a minimum, using assays. "If physicochemical and biological characterisation of the biosimilar and the reference LMWH has been performed with a high level of resolution and convincingly demonstrated close similarity, in vivo studies are not required as part of the comparability exercise," EMA explained. 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, 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.
Efficacy and Safety Considerations
Clinical studies represent something of a challenge to sponsors, EMA explained. "Due to the heterogeneity of LMWHs, conventional pharmacokinetic studies cannot be performed," it wrote. "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."
Generally, pharmacokinetic and pharmacodynamics properties of the similar biological medicinal product "should be compared to the reference product in a randomized, single-dose two-way crossover study in health volunteers using subcutaneous administration," EMA added. The equivalence margins between the two products should be specified before the starting of testing and be justified appropriately.
Efficacy, meanwhile, should be evaluated through a comparative clinical trial unless pre-clinical testing showed the two products to be similar to a high degree of certainty. This, however, would be an "Exceptional scenario since the required amount of reassurance from analytical data and bioassays would be considerable," EMA noted.
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 orthopedic 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.
As with the pharmacokinetic studies, equivalence margins will need to be defined in advance of the study and appropriately justified.
The study should assess any deep-vein thrombosis (DVTs) present using "state of the art imaging techniques," EMA added.
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. These events, such as major bleeding, should be classified and defined in advance to support consistency and relevancy.
Comments on the draft guideline are due on 31 July 2013.