Five main barriers to developing biosimilars

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According to Dr Ash Ramzan, principal consultant at Woodley BioReg, there are five main barriers preventing biosimilars from reaching their full potential.

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These five barriers include:

  • Intellectual property (IP) surrounding the originator biologicals
  • Limitations placed on biosimilar interchangeability, substitution and switching
  • Complex multi subunit or multimodal biologicals, e.g. antibody-drug conjugates [ADCs] and vaccines
  • Data requirements for registration, including analytical/biochemical, pre-clinical and clinical information
  • Other unknown considerations

Intellectual property
Developing an originator biological takes time and resources. Due to their complexity, research and development costs for a biological are often considerable. It is therefore not surprising that companies want to protect their investment. This is typically achieved through a period of market exclusivity assured through IP protection.

Due to the number and complexity of the patents protecting biologicals, this has led to a plethora of patent challenges from biosimilar makers in recent years. However, originator biological companies have come out fighting and have even been accused of using a ‘patent thicket’ of overlapping and add-on patents, as well as the litigation process itself, as a mechanism to protect their blockbusters [1]. Another way that originator companies have fought back is by making deals with potential competitors in a practice that has been called pay-for-delay. One such example of this is originator company AbbVie, which has now made nine deals with companies regarding biosimilars of its adalimumab biological, Humira [2]. The result of this is that, in the US, adalimumab biosimilars will be delayed until 2023, whereas in Europe they have been available since 2017 [3].

Interchangeability, substitution and switching
Interchangeability refers to the medical/pharmaceutical practice of switching one medicine for another that is equivalent, in a given clinical setting. In the European Union (EU) this is interpreted as the medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting on the initiative, or with the agreement of the prescriber. Whereas in the US, the interchangeable product may be substitutable for the reference product without the authorization of the healthcare prescriber [4].

In the EU, decisions on the interchangeability or substitution of biosimilars and originator biologicals are not made by European Medicines Agency (EMA), but at the national level [5]. Whereas in the US, even though the US Food and Drug Administration (FDA) has the authority to designate a biosimilar as interchangeable with its reference product, it has to date not yet designated a biosimilar as interchangeable.

Automatic substitution is the practice by which a medicinal product other than the one specified on the prescriptions is dispensed to the patient, without the prior informed consent of the treating physician. This is normally carried out by the pharmacists. Switching, on the other hand, is the decision by the treating physician to exchange one medicine for another medicine with the same therapeutic intent, e.g. from originator to generic/biosimilar or vice versa, in a patient during the course of treatment.

Complex biologicals
Given the intrinsic variability and complex structure-function relationship of biological molecules, the understanding of complex biologicals – including vaccines and multi-subunit molecules – by the industry and regulatory bodies is severely limited and the potential risks not sufficiently understood to be mitigated.

Such products have therefore not yet been allowed to be registered as biosimilars yet but continue to be developed.

Data requirements for registration
One of the key advantages of generics, and the reasons for their rapid growth and uptake, was the ability to register them without a full clinical development programme. Typically, only bioequivalence and bioavailability data are required.

However, when it comes to biosimilars, due to their complex nature, many of their effects cannot be fully or accurately determined through in vitro studies. This means that some degree of clinical equivalence or non-inferiority study is often required to demonstrate biosimilar equivalence to the originator biological.

Despite this additional burden, Dr Ramzan believes that ‘the development and registration of biosimilar products remain an attractive proposition for those manufacturers that are able to make, test and characterize such complex molecules under sterile conditions’.

Other unknown considerations
Finally, since biosimilars are still a relatively new entity, other unknown considerations are expected to be faced at some time in the future – and will need to be addressed accordingly.

According to Dr Ramzan, ‘as biosimilar products are an emerging treatment, there are many unknowns. This makes defining regulatory standards and controls difficult’.

In Europe, EMA has amassed more than 15 years of experience with the regulation of biosimilars and is constantly updating its guidelines to reflect improved understanding and methods of analysis. EMA issued its first guideline for the approval of biosimilars via an abbreviated registration process in 2005 and has since developed many general and specific guidelines for biosimilars [6]. It is also constantly updating these guidelines, taking into account input from industry [7].

Dr Ramzan concludes that there remain challenges, not least of which is ‘not only maintaining diligence and patient safety with the currently approved products, but the development of biosimilar registration packages for biological products of increasing complexity’. He ends by saying that ‘caution should be exercised throughout to ensure the correct balance between biosimilar development and patient safety’.

Editor’s comment
Readers interested to learn more about barriers facing biosimilars are invited to visit to view the following manuscripts published in GaBI Journal:

Barriers to market uptake of biosimilars in the US

Local policies on biosimilars: are they designed to optimize use of liberated resources?

GaBI Journal is indexed in Embase, Scopus, Emerging Sources Citation Index and more.

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1. GaBI Online - Generics and Biosimilars Initiative. AbbVie makes more deals delaying adalimumab biosimilars in the US []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jul 23]. Available from: 
2. GaBI Online - Generics and Biosimilars Initiative. Boehringer Ingelheim finally signs licensing deal for Humira biosimilar []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jul 23]. Available from: 
3. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jul 23]. Available from: 
4. GaBI Online - Generics and Biosimilars Initiative. Glossary of key terms []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jul 23]. Available from: 
5. GaBI Online - Generics and Biosimilars Initiative. Biosimilars and interchangeability []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jul 23]. Available from: 
6. GaBI Online - Generics and Biosimilars Initiative. EU guidelines for biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jul 23]. Available from: 
7. GaBI Online - Generics and Biosimilars Initiative. EMA continues to be open to alternative clinical development strategies for biosimilars []. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jul 23]. Available from:

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