Comparability studies and substitution of biosimilars

Biosimilars/Research | Posted 09/03/2012 post-comment0 Post your comment

In order to demonstrate similarity between the biosimilar and the biological reference product, both products must be compared to satisfy quality, safety and efficacy requirements [1].


The International Conference on Harmonization defines ‘comparable’ as products having highly similar quality before and after manufacturing process changes, without adverse impact on safety or efficacy and immunogenicity.

Under European and US rules, if the originator biological product has more than one indication, the efficacy and safety of the biosimilar must be justified or demonstrated separately for each indication. However, in Europe it may be possible to extrapolate from one indication to another, with this being carried out on a case-by-case basis.

New pharmacovigilance legislation was also adopted in 2010 in Europe requiring the applicant to present an extensive risk management plan (pharmacovigilance) taking into account potential risks [2]. Such an extensive plan is not yet mandatory in the US.

Some in the pharma industry, however, have called for ‘comparability’ to be replaced by ‘equivalence’, stating that the comparison of quality characteristics between the biosimilar and the reference product will always show differences. In fact, the biosimilar can also have improved quality compared to the originator. And with the improvement of analytical methods, our ability to find differences will only increase. In most cases, quality differences become irrelevant if the clinical data show the biosimilar to be clinically equivalent to the reference product [3].

Whether a biosimilar can be interchanged or substituted with its reference product is a subject that differs somewhat between Europe and the US.

In the US, FDA has the authority to designate a biosimilar as interchangeable with its reference product if the biosimilar is expected to produce the same effect as the originator product. This means that the biosimilar may be substituted for the originator product by the pharmacist without referring back to the prescriber [2].

In Europe, however, EMA does not have the authority to designate biosimilars as being interchangeable with the reference product [2]. This substitution issue has been left to the national governments in each Member State, although EMA recommends that such a decision must follow the opinion of a qualified healthcare professional.

Since biosimilar and biological reference medicines are similar but not identical, the question of substituting an expensive biological with a cheaper biosimilar is one that has to be considered carefully [1].

Related articles

Reimbursement of biosimilars

Pricing of biosimilars

Biosimilars: demonstrating ‘similarity’

Registration of biosimilars in Europe and the US

Factors affecting market access of biosimilars


1.  Simoens S, Verbeken G, Huys I. Market access of biosimilars: not only a cost issue. Oncologie. 2011;13(5):218-21.

2.  GaBI Online - Generics and Biosimilars Initiative. Practical guidance on new pharmacovigilance legislation []. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Mar 9]. Available from:

3.  GaBI Online - Generics and Biosimilars Initiative. What clinical trials will be required for biosimilar mAbs? []. Mol, Belgium: Pro Pharma Communications International; [cited 2012 Mar 9]. Available from:

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