Is a Biosimilar?
Unlike small molecule drug (SMD) generics, which are identical to their innovator drug, it is not possible to produce an identical copy of an innovator biologic due to their large size, complex structure, and manufacture in a unique living cell line. Instead, a biologic deemed to be “highly similar” to the innovator biologic is known as a biosimilar.
A biosimilar is a non‐innovator biologic or biotherapy that is “highly similar” to and has no clinically meaningful differences from an approved innovator (licensed or reference) product. Thus, a biosimilar is deemed as having no clinically meaningful differences to the innovator product in terms of purity, potency, and safety. Manufacturers are generally required to provide supporting evidence that standards for biosimilarity recommended by the World Health Organization (WHO) are met5 when seeking marketing approval from the USFDA, EMA, or other regulatory agencies.
Regulatory approval of a biosimilar involves a similarity exercise. This may include head‐to‐head comparability studies, and it is based on a totality of evidence concept6 that generates a hierarchy of data and evidence to support similarity with the originator product. To support biosimilarity, the product must be deemed “highly similar” to the reference product; demonstrated by extensively characterizing chemical identity (structure), purity, and bioactivity (function) of both the reference and the proposed biosimilar. Minor differences between the reference product and the proposed biosimilar product in clinically inactive components are acceptable. There are similarities at molecular and structural levels or critical quality attributes (CQAs) between the reference and biosimilar products are similar.7
CQAs are divided into four separate categories: content‐related attributes such as protein content; structural attributes; isoform profile; and, impurities and biological activity.8
Development of biosimilars is therefore methodologically complex, and it has been remarked that biosimilar development is an “imitation game.”9 A biosimilarity index (based on reproducibility probability) has been proposed to assess biosimilarity.10 In summary, biosimilars are approved by showing “near fingerprint identity,” but the term “near” is not absolute. Highly similar implies (but does not prove) therapeutic equivalency.
The targeted quality profile of biosimilars is strictly defined by the originator's product characteristics.11 Typically, over time, since the original biologic was introduced, many product enhancements and efficiencies would have been achieved. Moreover, cell lines change over time. An important question, therefore, has been posed: “Is a biologic produced 15 years ago, a biosimilar of itself today?”12. In fact, it is hard to envisage that an originator biologic manufactured today would be able to demonstrate similarity to its product manufactured 15 years previously. Therefore, a global reference comparator for each biologic for biosimilar development and testing has been proposed.13 Mandatory deposit of the original biologic's cell line with the regulator at the time of its approval has been suggested as a remedy.14 The paradox of sharing the same therapeutic (and adverse) action without full (absolute) chemical identity has also been raised and is the subject of lively debate.15
Other terms used in the literature for biosimilars include follow‐on biologics, similar biotherapeutic products (SBPs) or subsequent‐entry biologics (SEBs) as used by the regulatory authority in Canada16 or non‐original biologics (NOBs). Bio‐mimics is also used, but the production of exact molecular copies of biologics (bio‐copies) is almost impossible and biosimilars are not replicas of innovator biologics and cannot be regarded as (or be confused with) SMD generics and are not bio‐generics. Biosimilar definitions in major regulatory jurisdictions are summarized in Table 1.2.
Questions posed in the biosimilar literature include: are biosimilars identical twins or just siblings; when are biosimilars similar enough17; are biosimilars “bio‐same or bio‐different18 how dissimilarly similar are biosimilars19; biosimilars – how similar or dissimilar are they20,21; how far does similarity go; should the term semi‐similars be used instead of biosimilars26 or are they overpriced me‐toos?”27. It has also been asked, “if biosimilars are patentable?”28.
Some emotive language has also crept into the literature; some fear the adoption of biosimilars while others see it as an opportunity.29
The above discussion highlights that internationally accepted terminology is important for biosimilars. An excellent resource on the language of biosimilars is available for historical and contemporary context.30
Table 1.2 Definitions of biosimilars by major regulatory agencies.
| Regulatory agency/Country | Definition |
|---|---|
| European Medicines Agency, EMA | Biologic product is similar to another biologic already authorized for use |
| World Health Organization, WHO | Biotherapeutic product that is similar (quality, safety, and efficacy) to the licensed reference product |
| Food and Drug Administration, FDA (USA) | A biologic product that is highly similar to the reference product in safety, purity, and potency; minor differences in clinically inactive components are acceptable |
| Biologics and Genetic Therapies Directorate, BGTD (Canada) | A biologic entering the market after a version previously authorized; demonstrated similarity to reference |
| Pharmaceuticals and Medical Devices Agency, PMDA (Japan) | A biotechnological drug developed by a different company, comparable to an approved biotechnology product |
| Therapeutic Goods Administration, TGA (Australia) | A version of already registered biologic with demonstrated similarity in physicochemical, biologic, and immunologic characteristics (efficacy, safety) based on comparability exercise |
1.3.3 What Is a Biobetter?
Biobetters are related to existing biologics by the target of action but have been intentionally improved in manufacturing attributes, disposition/pharmacokinetics, efficacy, safety, or enhanced stability.31 Biobetters build on the success of an approved innovator biologic or biosimilar but possess a lower commercial risk for biotechnology companies than a novel class of biologic. Biobetters are also known as second‐generation biologics.
Biobetters improve on the relevant property of biologics. Many innovator biologics or biosimilars have less than optimal pharmacokinetic properties (e.g. high clearances or short half‐lives). Besides, almost all these proteins are dosed parenterally by injection rather than orally. Thus, modifications to improve their pharmacokinetic behavior have led to biobetters. Examples include pegylated longer half‐life version of filgrastim or a more extended half‐life version of epoetin α, using fusion proteins.
While biosimilars are comparable to the originator product in terms of quality, safety, and efficacy, biobetters incorporate intentional modifications to the innovator's molecular profile. This distinction between biosimilars and biobetters has essential implications from a regulatory perspective. Biosimilars follow class‐specific regulatory guidance whereas biobetters are considered as new molecular entities and have registration requirements of a new drug.
Biobetters may have advantages
