Biosimilars: Concepts and controversies.

Biosimilars are copies of reference biological drugs, developed as the patents for original biologicals expire. They are thus developed to replicate an original biological medicine just a generics are intended to replicate a chemically-synthesized medicine; however, there are important technical and regulatory differences between the two. Unlike chemical drugs, molecular identity cannot generally be established for any two biological drugs. Accordingly, their pharmacological properties cannot be assumed to be the same. This is due to the complexity of the production of biologicals and to the presence of minor natural variations in the molecular structure (collectively known as microheterogeneity). Further, biological production yields slightly different versions of the drug over time, particularly when changes are introduced in the production process. In this case the prechange and postchange versions of the biological are analyzed in what is called a comparability exercise. The comparable versions thus validated are considered not to have any significant differences at the clinical level. Likewise, biosimilars are not identical copies but comparable versions of the original biological drug, also validated through a comparability exercise, although of a much broader scope. Although current knowledge about biosimilars has increased significantly, they still arise a number of controversies and misconceptions, particularly regarding issues like extrapolation of indications, immunogenicity and substitution. This review deals with concepts and controversies in the biosimilar field.