Despite the EMEA’s European Public Assessment Reports, in which comparability of the quality, safety and efficacy of biosimilars to their reference products is shown, clinicians should be aware of issues that may emerge during the development and approval of these products, which highlight the challenges of biosimilars.

For example, the EMEA has approved two biosimilar somatropins, Omnitrope of Sandoz (manufactured with recombinant DNA technology in E. coli bacteria) and Valtropin of Biopartners (manufactured with recombinant DNA technology in the yeast Saccharomyces cerevisiae).

The comparability of Omnitrope, a biosimilar version of the recombinant human somatropin Genotropin of Pfizer, was shown in a randomised controlled trial in 89 children with a lack of growth hormone, with an additional safety study in 51 children. And Valtropin, a biosimilar version of Humatrope of BioPartner, was shown to have a similar efficacy and safety as its reference product in a 12-month randomised controlled trial involving 149 children lacking growth hormone.

However, during the development of the biosimilar Omnitrope, an immunogenicity issue occurred with an early version of the product. Up to 60 percent of the patients enrolled in two clinical studies developed anti-growth hormone antibodies, which did not appear to affect growth rate. The cause of immunogenicity was linked to excess host cell protein contamination, which was resolved by the manufacturer with additional purification steps.

Another example is a problem with a biosimilar recombinant human erythropoietin (rHuEPO). The EMEA has approved five biosimilar rHuEPOs. Abseamed, Binocrit and Epoetin alfa Hexal are biosimilar versions of the epoetin alfa reference product Eprex, all manufactured by Rentschler Biotechnologie but marketed by three different companies. These biosimilars were shown to be comparable to Eprex in quality, safety and efficacy. However, immunoaffinity chromatography showed different glycosylation patterns: the biosimilars had higher levels of high-mannose-type structures. The comparability in safety and efficacy to the reference product was shown in a randomised controlled trial with 479 haemodialysis patients with renal anaemia and a study with 114 cancer patients getting chemotherapy, but this should have been shown with two randomised nephrology trials.

For two additional biosimilar versions of Eprex, Retacrit and Silapo, manufactured by Norbitec and marketed by STADA, the epoetin alfpha Eprex was used as the reference product, though the International Nonproprietary Name (INN) for these biosimilars is epoetin zeta. The active substance of epoetin zeta was shown to be a representative of the active substance found in Eprex and the protein structures were comparable. However, differences were found in the glycosylation profile with respect to glycoforms without an O-glycan chain and variant of sialic acid, and a different immunogenicity profile was obtained in dogs.

The comparability of epoetin zeta to Eprex was shown in two randomised clinical trials, a correction phase study and a maintenance phase study, involving 922 haemodialysis patients with renal anaemia. Comparability was not shown for mean dosage during the evaluation period and a possible difference in the bioactivity of epoetin zeta and Eprex was suggested. Fortunately, thanks to its unique INN, epoetin zeta is more readily distinguished from other epoetins.

The EMEA has also recently approved biosimilar filgrastims for the treatment of neutropenia – Ratiograstim and Filgrastim Ratiopharm of Ratiopharm, Biograstim of CT Arzneimittel, Tevagrastim of Teva, Zarzio of Sandoz and Filgrastim Hexal of Hexal – that were shown to be similar to their reference product Neupogen of Amgen.

It is important to recognise that the EMEA provides a rigorous and balanced approach to the biosimilars approval process. Regulators are attempting to meet the demands of the healthcare market while ensuring the quality and safety of biopharmaceuticals. The approval of biosimilar products does not substantiate interchangeability with reference products.

Furthermore, the EMEA has not approved all biosimilar applications. For example, Alpheon, a biosimilar version of Roferon-A (interferon alfa 2a) was recently rejected because of quality and clinical differences with the reference product, inadequate data on the stability of the active substance, inadequate validation of the process and insufficient validation of immunogenicity testing.