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Innovator Biologics, Biosimilars, and Biobetters: Terminology, Nomenclature, and Definitions

Iqbal Ramzan

Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

KEY POINTS

• Many different terms are used for innovator biologics, biosimilars, and biobetters internationally.
• Greater harmonization of terminology, definitions, and nomenclature across different regulatory jurisdictions and countries would assist health practitioners and patients in understanding the complex issues of biologic medicines.
• The salient language of innovator biologics, biosimilars, and biobetters are introduced in this chapter to set the context for the rest of the book, which deals with specific issues in greater detail pitched at pharmacists, doctors, and patients.

Abbreviations

Abbreviation Full name ABPI Association of British Pharmaceutical Industry AfPA Alliance for Patient Access BAP Biosimilars Action Plan BLA Biologics License Application BPC Biologics Prescribers Collaborative BPCI Act Biologics Price Competition and Innovation Act CAR-T Chimeric Antigen Receptor Therapy CHMP Committee for Medicinal Products for Human Use (EMA) CIOMS Council of International Organizations of Medical Sciences CQAs Critical Quality Attributes CVMP Committee for Medicinal Products for Veterinary Use Da Dalton DNA Deoxyribonucleic Acid EMA European Medicines Agency EPAR European Public Assessment Report EU European Union FDA Food and Drug Administration GABi/GaBI Generics and Biosimilars Initiative LDN Limited Distribution Network mAbs monoclonal Antibodies NHS National Health Service NICE National Institute for Clinical Excellence NMS Non-Medical Switching NOBs Non-Original Biologics PBS Pharmaceutical Benefits Scheme P&T Pharmacy & Therapeutics (Committee) PTMs Post-Translational Modifications QbD Quality by Design QUM Quality Use of Medicine RMP Risk Management Plan RPS Reference Product Sponsor RWE Real-World Evidence SEBs Subsequent-Entry Biologics SMD Small Molecule Drug UMC Uppsala Monitoring Centre UNESCO United Nations Educational, Scientific and Cultural Organization USA United States of America USD US Dollar WHO World Health Organisation

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...