What Are the Eight Barriers to Biosimilar Development?

The Center for Biosimilars Staff

Quality, safety, and knowledge are critical.

In a report published by the Journal of Pharmacovigilance in 2015, the top eight barriers to the development and access of biosimilars are highlighted. Drug quality, safety and the population health needs, a deep knowledge of biosimilar development, as well as joint effort of the manufacturers and their will to share the critical development data are some of the primary concerns:


Changes to the manufacturing process of biosimilars compared to their original counterpart aren’t advised, but changes are somehow inevitable as the manufacturing data for the reference product is not accessible for the biosimilar manufacturers, as it is property of the innovator manufacturer, even after the patent expiry. Modifications can also be made to improve the quality, efficiency and reliability of the manufacturing process or the end product. These changes may lead to structural differences, resulting in efficacy modifications and with potential insurgence of adverse effects, i.e., immunogenicity. In these cases, further non-clinical and clinical evaluations might be needed to evaluate the product, depending on the extent of modifications.

Extrapolation of Indications

The extrapolation across indications is a concept pointing that, when the clinical data for a biological drug is generated for one therapeutical indication, they can be extrapolated to other indications, taking into account, for the drug efficacy and safety, of the overall information gained from the comparability exercise.

In the context of biosimilars, extrapolation from one indication to another may be considered if biosimilarity to the reference product has a comprehensive comparability, including efficacy, safety and immunogenicity, suitable to detect clinically relevant differences, in particular if the mechanism of action of the active substance and the target receptor(s) is the same. In Europe, this concept has been successfully implemented with biosimilars of EPO, filgrastim and infliximab.


Beside the biotechnological product involved, it is important to consider other factors that can be potentially immunogenic, such as the variation in the glycosylation pattern, denaturation or aggregation, the presence of impurities in the solution, dose, route of administration, treatment duration and genetic characteristics of patients. Hence, the immunogenicity of a biosimilar must always be deeply investigated.


Manufacturers need to plan an extended post-market surveillance, that is very important to grab the immunogenic phenomenon, as well as efficacy in the different diseases. The biosimilar guidelines state that the pharmacovigilance plan should be included in the data submitted for the registration of a biosimilar.


Products approved for the same indication can be considered interchangeable and used for the said indication. This is not to be confused with the term substitutable, which refers to the product that can be used in lieu of another during the same therapeutical treatment.

Generic drugs are usually considered therapeutically equivalent with their reference products. In these cases, substitution is permitted. As already underlined, biotechnological drugs are distinct from chemical drugs and it’s difficult that two biologic drugs could be exactly the same. It is widely agreed by a broad consensus of the scientific, regulatory and industry communities, that biotechnological drugs have the potential to present unique risks when switched, without involving the prescribing physician.


WHO has proposed the Biological Qualifier scheme, applicable to all biological substances assigned INN’s, which can be adopted on a voluntary basis by any Regulatory Authority. This scheme will assign a code of four letters at random to complement the INN for a biological compound and it will uniquely identify directly or indirectly the manufacturer and manufacturing site of the active substance in a biological product.

Patient and Clinician Awareness

Efficacy and safety are the primary concerns. Since the active substance of a biosimilar is not identical to the active substance of the reference product, the regulatory requirements for approval of generics are inadequate to demonstrate the quality, efficacy, and safety of biosimilars.

The clinicians often look at clinical data to determine the efficacy and safety of a drug. For biosimilars, in some cases, the clinical data can be reduced, if the comparison of structural and functional characteristics is comprehensive. Moreover, in some Countries, problems have been reported on biological drugs which are erroneously called biosimilars, due to the inconsistent use of the terminology. Sometimes, clinicians are just not well informed about the scientific concept regarding the development and licensing of biosimilars. This can lead to the fear of their use for some of proposed indications, especially for those for which no specific clinical trials have been performed, but data are extrapolated based on the efficacy and safety for other indications.

Time and Cost

Biosimilars can lead to significant cost reductions, not only for the final recipients, but also for governing authorities who have reimbursement policies for the pharmaceuticals. Each Regulatory Authority has its own guidelines for the comparability of biosimilar to its reference product. These differences make hard for the manufacturing companies to reduce the productive costs of these products, as they may have to establish different comparison in different countries.