Biosimilar Products or Follow-On Biologics
               Biosimilar products or follow-on biologics or whatever such products will be called when they grow up and enter the world of commerce appear to be gaining increased attention.  It is my opinion that part of this interest comes from the generic drug industry, part of this comes from price pressures that are coming irrespective of political posturing, and part from an profound lack of creativity in the biotechnology industry.   As I have previously stated elsewhere, your corporate position will depend on whether you are playing offense (developing biosimilar) or defense (protecting currently licensed product). This, of course, uses the football analogy that I used in Bioprocess International several years ago (1).   The Europeans are ahead of the United States on the problem of biosimilars because, in what they consider real football, their offensive and defensive players are on the field at the same time and don't have to go through ritual change of personnel on change of possession; there is also a single individual responsible for protecting the goal.   This latter consideration is of importance for the large company which has a licensed product but excess capacity which they wish to use to manufacture a biosimilar (hopefully not biosimilar to their licensed product).   This situation could lead to the left hand not knowing what the right hand is doing but without the positive connotation (see Matthew 6:3).
            Approval of biosimilar products will depend on the demonstration of comparability.  Now, it is my sense that a thorough demonstration of comparability may only be demonstrated after considerable clinical experience (Phase IV surveillance) such as that performed to evaluate the formation of factor VIII inhibitors in hemophilia A treatment (2).  However, a reasonable amount of preclinical study should permit entrance of a biosimilar product into clinical study.  There is a large menu of physical and chemical techniques which can be used to evaluate the physical and chemical similarity of a biosimilar product with a licensed product (3).  Argument has been presented that formulation issues prevent the accurate comparison of final drug product as compared to bulk drug product (4).  A recent paper by Cauchy and Hefford (5) has challenged this conclusion.  Duconge (6) has raised the issue of the significance of product equivalence  studies  in a paper which, as far as I can tell, has "flown under the radar screens." Finally, the issue of unique post-translational modification, most notably glycosylation, is frequently invoked as a "game-stopper" in issues of comparability.  I note that recombinant factor VIII preparations which differ in host cell source (BHK versus CHO) and presumably purification and formulation do differ in glycosylation without differences in therapeutic utility (7).
            There is considerable ground to be covered in the continuing saga of biosimilar products and I would hope that such work will be based on science rather than marketing.
References
1. Lundblad, R.L., Throwing the flag on biosimilars, Bioprocess International, March, 2008).   
2.  Den Uijl, I., Mauser-Bunschoten, E.P., Roosendaal, G., et al., Efficacy assessment of a new clotting factor concentrate in haemophilia A patients,  including prophylactic treatment, Haemophilia  15, 1215-1218, 2009.
3.  Lundblad , R.L., Approaches to the Conformational Analysis of Biopharmaceuticals,  CRC Press, Boca Raton, Florida, 2010.
4. Heavner, G.A., Arakawa, T., Philo, J.S., et al., Protein isolated from biopharmaceutical formulations cannot be used for comparative studies: Follow-up to "A case study using Epoetin Alaph from Epogen and EPREX," J.Pharm.Sci. 96, 3214-3225, 2007.
5. Cauchy, M. and Hefford, M.A., Excipient exchange in the comparison of preparations of the same biologic made by different manufacturing processes: An exploratory study with recombinant human growth hormone (rhGH), Biologicals 38, 637-643, 2010.
6. Duconge, J., The case of biotech-derived product equivalence: Much ado about nothing, Curr.Clin.Pharmacol. 1, 147-156, 2006.
7. Lundblad, R.L. and Bradshaw, R.A., Addressing Product Improvement Using Chemical Modification  in Biopharmaceutical Manufacture.  A case study in blood coagulation factor VIII, Bioprocess International, September 2006.