Biosimilar Insulin: Not a Piece of Cake
As of now, all of the insulins available on the EU market were approved using the standard pathway for new drugs. Only one company attempted to enter the EU insulin market through the biosimilar route, and it failed. Marvel Lifesciences applied in 2007, claiming their insulin formulations were similar to Lilly's Humulin.
There were numerous problems with the application: Critical information was missing, ranging from tracking numbers on product lots to chemical analysis on lots used in the PK, PD, and safety trials. The trials themselves were too short, and poorer performance versus reference in PK and safety trials did not help their case.
Another company, Biocon, recently ended its year-old collaboration with Pfizer to bring biosimilar insulin to markets; Biocon will be left to fend for itself in this regard. I don't anticipate them having too much trouble getting approval, but they may have to wait: New guidelines for insulin analogues haven't been released yet (the commentary ended last year).
Even so, one wonders, why are trials necessary? Wouldn't proof of identical composition be sufficient? Such proof is not forthcoming. Biologics are too large to examine every atom and their source processes too variable to be assured that a biosimilar is indeed identical. A small amount of protein background might be permissible with one host organism, but immunogenic with another. Host organisms can decorate their protein products differently, leaving different sugar chains or amino acid modifications. In some cases, different glycosylation patterns can be advantageous, producing a longer-lasting product, but these changes also mean that previous data on pharmacokinetics no longer applies and dosing regimens would have to be adjusted.
Finally, considerations such as protein aggregation and misfolding mean that changes in product packaging can have more severe results than they would with small molecule drugs. In 1998, the epoetin-alpha product Eprex was switched from human serum albumin buffer to polysorbate-80 and glycine. It is suspected that the subsequent increase in protein aggregation in transit/storage led to greater immunogenicity and caused a sudden rise in cases of antibody-mediated pure red cell aplasia, a serious and potentially lethal autoimmune disease. Post-market surveillance caught this, and the contraindication of subcutaneous administration (generally more immunogenic) prevented more cases.