1.1 Place of Biologics in Modern Therapeutics
Biologic therapies have entirely revolutionized the treatment of many debilitating, life‐changing chronic autoimmune diseases like rheumatic arthritis and plaque psoriasis as well as life‐threatening cancers for which no viable treatment option has existed previously. They also play a critical therapeutic role in many endocrine disorders and neurodegenerative conditions. Biologics are the fastest growing sector of the drug market1 and are also the most expensive therapies. As a result, “highly similar” versions of innovator biologics, biosimilars have been introduced to provide cost‐effective biologic treatments.
The first innovator biologic was introduced ~40 years ago, and the first biosimilar was introduced in the European Union (EU) and United States (USA) in 2006 and 2015, respectively. Currently, there are over 300 biologics registered worldwide and the EU has over 60 approved biosimilars. In the United States, biosimilars are an emerging market, with 19 approved biosimilars. Biosimilar market access comparison between the United States and EU has shown that market access in the United States is less favorable. This is due to many factors including lack of incentives to prescribe biosimilars in the United States and small price discounts of biosimilars compared to innovator biologics.2
In many countries, including Australia and emerging pharmaceutical markets like Brazil, biosimilar use is actively encouraged as governments attempt to contain the costs of expensive innovator biologics. Assuming discounts on off‐patent innovator biologics and biosimilars of ~50%, it is predicted that by 2020 there will be annual savings of over €8–10 billion in the EU.3
Biologics are complex proteins or protein‐like molecules produced using biotechnology techniques in living cells. Their structural, functional, and manufacturing processes lead to clinical concerns/controversy about their efficacy and safety, including the potential for treatment failure and severe immunogenicity reactions. Pharmacists, doctors, and other health professionals, therefore, need to be fully conversant with all aspects of their clinical utility.
1.2 Background to Terminology, Nomenclature, and Definitions
In the biologics field, there are international differences in the various terms, definitions, and abbreviations that are used. This arises due to country/continent differences, different regulatory and policy frameworks, and the specific requirements of the various regulatory agencies.
Definitions, nomenclature, and terminology on biologics will now be reviewed in detail so there is a common understanding among readers.
1.3 Innovator Biologics, Biosimilars, and Biobetters
1.3.1 What Is a Biologic Medicine?
Biologic medicines are active substances made by or derived from a biological source, rather than a chemical source, or synthesized chemically. Biologic medicines are also known as biopharmaceuticals or biotherapies and they are comprised of proteins such as vaccines, hormones, enzymes, blood products, allergenic extracts, monoclonal antibodies (mAbs), human cells and tissues, and gene therapies (Table 1.1). Typically, biologics are proteins or protein‐containing fragments. The first biologic (recombinant human insulin) was approved in 1982.4
When a biological medicine is administered to a patient, the expectation is that it will function as the natural endogenous protein, resolving clinical symptoms and either preventing or slowing the progression of the disease process. The mechanism(s) by which biologic medicines produce their clinical effects varies from product to product and across different clinical indications and diseases. Biologics may be tailor‐made to target the desired receptor or cells in the body.
Table 1.1 Broad categories of biologic medicines.
| Biologic | Description |
|---|---|
| Hormone | A substance (peptide or steroid) produced by a tissue or organ to elicit a physiologic action |
| Vaccine | An agent containing an antigen (live, killed, or attenuated pathogenic agent) to stimulate the immune system |
| Interferons | Proteins produced by cells in response to bacterial or viral infections |
| Growth factors | A substance that promotes growth, especially cellular growth |
| Polypeptides | Peptides containing from 10 to 50 amino acids |
| Proteins | Naturally occurring or synthetic polypeptides generally of 10 kDa in size |
| Monoclonal antibodies (MAbs) | A single synthetic immunoglobulin produced by recombinant techniques directed against a single antigen or endogenous molecule |
| Interleukins | Group of cytokine proteins |
| Cellular and tissue biotherapies | Like CAR‐T |
| Emerging biotherapies | Like antibody–drug conjugates or bispecific antibodies |
Terms like “de novo biologic drugs” or “bio‐originators” have also been used in the biologics literature. The first (initial) biologic medicine belonging to a specific class or category to be approved and registered (and/or marketed) is known as an innovator biologic or the biologic reference product. The term originator biologic is also used.
Biotechnology techniques are increasingly associated with the production of most biologic medicines. Biotechnology is the application of bioengineering techniques to manipulate living organisms such as bacteria or yeasts or living cells, of bacterial, animal, or human origin to produce biologic compounds for medicinal or other purposes. Genetic engineering is used to produce the required molecules or proteins of interest. The cells have their genes altered or modified, using recombinant DNA techniques so that they produce a specific substance or perform a specific function, that is, the genes for a particular protein are introduced into the genes of a host cell, which then produces the specific protein of interest.
Each innovator biologic manufacturer has its unique cell line and manufacturing process. The production processes are precisely controlled to guarantee the quality and consistency of the final product. The production of biologic medicines is complex and requires a very high level of technical expertise and numerous (hundreds or thousands) of in‐process tests during product development and manufacture.
1.3.2 What 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.