Latest EU Guidelines For Biosimilars Dissected

Aug 01, 2010
Volume 22, Issue 8

The full version of this biosimilars feature can be read in the August issue of our digital magazine: http://www.pharmtech.com/ptedigital0810

Peter Gaskin
The European Medicines Agency (EMA) adopted the Guideline on Similar Biological Medical Products in 2005 and the first biosimilar product (Omnitrope; Sandoz GmbH, Switzerland) was subsequently marketed in Europe in 2006.1,2 The guideline still provides overarching guidance, but since its introduction the EMA has developed a range of more specific guidelines that provide details for different product classes of biosimilars.

Low molecular weight heparins

To date, guidelines have been adopted for biosimilar insulin, somatropin, granulocyte colony-stimulating factor, erythropoietin and, most recently, low molecular weight heparins (LMWHs). Unlike other biosimilar guidelines, the guideline concerning LMWHs specifically states that conventional pharmacokinetic studies are not required because of the problems in developing bioanalytical assays for LMWHs;3 instead, pharmacodynamic assessment of antiFXa and antiFIIa is recommended. It is also obligatory to monitor patient platelet counts regularly and to test for PF4heparin complex-antibodies in those who develop the rare, but serious side effects of thrombocytopenia or thromboembolic complications when using LMWHs.

Interferon alpha

The EMA has published a reflection paper that lays down key considerations for developing biosimilar interferon alpha products.4 The paper suggests a range of animal pharmacodynamic models that might be suitable for the assessment of interferon alpha products for different clinical indications, and also explains that a 4week toxicity study in Syrian Golden hamsters should be sufficient to meet requirements. The reflection paper does not give margins for the demonstration of pharmacodynamic or pharmacokinetic bioequivalence, stating merely that margins should be developed prior to testing and appropriately justified. However, the paper is more helpful on the issue of pharmacodynamic testing as it suggests a range of markers for consideration. Finally, the paper also provides useful advice on clinical study design and importantly suggests that extrapolation from one clinical indication to another may be possible if mechanistically justifiable.


Recently, a revision to the EMA's guideline on the non-clinical and clinical development of biosimilar erythropoietins was also made to indicate that extrapolation from one clinical indication to another could be made in the case of this product class, too.5 Indeed, based on the mechanism of action of these products this should be more straightforward than for interferon alpha products, where the mechanisms of action can be less well understood. The change in the guideline broadens the potential market for erythropoietin biosimilar products, without requiring further clinical studies in related indications.

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