The concept of biosimilarity
Biosimilar drugs were first introduced in Europe in 2006 . Their use in regular clinical practice has grown rapidly and health care professionals now need to have a good understanding of these products , their naming conventions and nomenclature and the key issues surrounding their development
Ryan Haumschild PharmD MS MBA Emory Healthcare and Winship Cancer Institute Atlanta , GA , USA
Biologic drugs , also known as biopharmaceuticals , biologics or biotechnological medicines , are genetically engineered proteins produced in living organisms such as bacteria , yeast , or mammalian cell lines using cell culture techniques ( see chapter on manufacturing in this handbook ). Typically , biologics are very large molecules of significant molecular weight . Generic small molecule pharmaceuticals are chemically synthesised and are identical to the originator molecules but it is not possible for a different manufacturer to produce an identical copy of an originator biologic ( also known as the reference product ( RP )) due to their large size , complex structure , and manufacture in a unique line of living cells . 1
Furthermore , biologics – such as monoclonal antibodies – are always heterogeneous mixtures . The final mix depends on the processes for synthesis and purification but can often contain 10 – 20 different variants or isoforms .
Thus , batch-to-batch variation is a particular problem for original biologic products , especially if there are variations in the manufacturing process , however minor ( e . g ., changes in pH , temperature , production volume , etc .). 2 Because of these considerations , follow-on products cannot be defined as ‘ biogenerics ’. Instead , a biologic deemed ‘ highly similar ’ to a reference biologic , already licensed by the US FDA or European Medicines Agency , and having no clinically meaningful differences is called a ‘ biosimilar ’. There can be minor differences in some clinically inactive components between the biosimilar and RP , but they must be highly similar in purity and potency , equivalent in efficacy and comparable in terms of safety . 3
The formal definition of a biosimilar is : A biological product developed such that there are “ no clinically meaningful differences between the biological product and the reference [ originator ] product in terms of safety , purity , and potency ” and “ demonstrates similarity to the [ originator ] in terms of quality characteristics , biological activity , safety , and efficacy based on a comprehensive comparability exercise .” 4 , 5
As a follow-on biologic can never be identical to the originator RP , the manufacturer is required to demonstrate that its product is ‘ highly similar ’ to the reference product by extensively analysing the structure and function of both the RP and the proposed biosimilar ( see chapter on key concepts in development ). Characteristics of the products such as purity , chemical identity , and bioactivity are compared . Minor differences between the RP and the proposed biosimilar product in clinically inactive components are acceptable .
For example , these could include minor differences in the stabiliser or buffer compared to what is used in the RP .
Biobetters One of the strategies that has been developed by manufacturers to fend off biosimilar competition is to develop related biologics that have been ‘ improved ’ from the originator biologic . Often referred to as ‘ biobetters ’, these improvements could include new strengths or formulations that could impact the route or rate of administration , the tolerability of the product , or the duration of action ( for example , pegylation to increase half-life ). 6 These biobetter products are not biosimilars because they are not expected to produce the same clinical efficacy and safety as the RP . 6
Bioidentical products Bioidentical products are not biosimilars but products based on the same regulatory dossier ( same date of authorisation ) an and manufactured in the same cell line , following the same process as the originator product . These ‘ bioidenticals ’ are the same products but with different brand names and are marketed by different manufacturers . Because they are the same products substitution at the pharmacy level is possible . However , it is not always easy for physicians and pharmacists to know which products are bioidenticals because this information is not usually part of the label .
The situation is made slightly more complicated because the term ‘ bioidentical ’ is often used in other contexts to indicate that , for example , a hormone used for postmenopausal hormone replacement therapy is the same as the naturally occurring hormone . 7
Naming conventions and guidelines Questions of nomenclature and traceability of biosimilars remain important issues for clinical development , licensing , prescribing , pharmacovigilance and identification of counterfeits . For pharmacovigilance purposes , it is essential to know exactly which product has been administered to a patient . Under the current system , different biosimilar products have the same international non-proprietary name ( INN ). Non-proprietary names that are unique and globally recognised for all pharmaceutical substances are assigned by the International Non-proprietary Names ( INN ) Programme of the World Health Organization ( WHO ). 8
How should biosimilars be named ? Naming should :
• Show that the RP and biosimilar are highly similar , but not identical
4 | hospitalpharmacyeurope . com