Handbook for health care professionals on biosimilar biologic drugs: About biologic drugs and biosimilars

On this page

• Introduction
• About biologic drugs
• About biosimilars

Introduction

Biologic drugs are used to manage various complex diseases and medical conditions.

Health Canada and international drug regulatory authorities use the term "biosimilar". It describes a biologic drug that receives market authorization based on a demonstrated high degree of similarity to its reference biologic drug. This demonstration of similarity allows the manufacturer to support authorization of that particular drug by:

• partially relying on relevant, known information about the reference biologic drug
• seeking authorization based on a reduced non-clinical and clinical data package

Health care professionals need sufficient information on biosimilars so that they can confidently prescribe and manage the use of these products in patient care. This handbook provides objective, evidence-based information on biosimilar:

• development
• authorization
• potential use

This will help in patient care decisions and counselling.

About biologic drugs

General

Biologic drugs are isolated or manufactured using living organisms, such as:

• cell lines
• bacteria
• animal or human tissues

Many biologic drugs are produced by recombinant DNA technology that enables the manufacturing of therapeutic proteins using living cells. When compared to chemically synthesized drugs, biologic drugs consist of larger and more complex molecules (refer to Figure 1).

Biologic drugs typically undergo extensive analyses of their physicochemical, structural and functional properties using state-of-the-art methods. This confirms that their quality profile will ensure the drug's consistency, safety and efficacy.

Biologic drugs are sensitive to different:

• chemical conditions, like pH and salt
• physical conditions, like temperature and light

They're also susceptible to microbial contamination and potentially harmful agents, such as viruses, during manufacturing. Therefore, manufacturers rely on very complex and tightly controlled processes to ensure the high quality of the therapeutic drug.

Due to these risks, careful attention is paid to:

• the quality and control of raw materials
• the capabilities of the manufacturing processes to remove potentially harmful agents
• testing of the biologic drug

Changes to the following factors can cause significant unexpected or unintended changes to the final product:

• facilities
• equipment
• source materials
• manufacturing processes

For these reasons, all biologic drugs used in Canada are subject to strict regulatory oversight to ensure their quality, safety and efficacy.

Please note: Aspirin (acetyl salicylic acid) is a registered trademark of Bayer.

Source: Mellstedt, H. (2013). Clinical considerations for biosimilar antibodies. European Journal of Cancer Supplements. 11 (3), 1-11. This figure is from Hakan Mellstedt, Leigh Revers and Eva Furczon, and is licensed under CC BY-NC-ND 3.0.

Figure 1 - Text description

Biosimilars are shown as larger and structurally more complex than a common pharmaceutical. For example, acetyl salicylic acid, which is not a biologic drug, is 180 daltons, while the biologic drug insulin is 5,808 daltons and the biologic drug Erythropoetin is 30,400. A monocolonal antibody (IgG1), a more complex biologic drug, is about 150,000 daltons.

Types of biologic drugs

The classification of biologic drugs encompasses a large number of drugs and groups of drugs. Many of these classes of biologic drugs are made using recombinant DNA technology.

Biologic drugs include:

• enzymes
• cytokines
• hormones
• allergenic extracts
• monoclonal antibodies
• low molecular weight heparins
• vaccines and other immunizing agents

The Biologic and Radiopharmaceutical Drugs Directorate (BRDD) within Health Canada's Health Products and Food Branch is the regulator of biologic drugs for human use. It provides regulatory oversight for biologic drugs with its comprehensive reviews of biologic drug submissions covering quality, safety and efficacy.

Under the Food and Drug Regulations, manufacturers must file a new drug submission (NDS) to Health Canada to apply for an authorization to sell that drug in Canada. An NDS must contain sufficient information and data to demonstrate the quality, safety and efficacy of the new drug.

Health Canada has no authority to grant market authorization to any drug independent of an application from the manufacturer. The market authorization process is completely dependent on the receipt and review of an NDS filed by the manufacturer.

About biosimilars

A biosimilar biologic drug, or biosimilar, is a biologic drug that's highly similar to a qualifying biologic drug that was already authorized for sale (known as the reference biologic drug or originator biologic). Biosimilars cannot themselves serve as a reference biologic drug for a subsequent biosimilar.

For a biosimilar drug to be approved for sale in Canada, its drug submission must meet the requirements of certain intellectual property regulations that relate to patents and data protection. These can grant time-limited market exclusivity to the reference biologic drug.

Biosimilars are developed with the goal of manufacturing therapeutic molecules with highly similar structural and functional profiles to their reference biologic drug. A biosimilar may contain different non-medicinal ingredients than its reference biologic drug. Due to the complexity of biologic drugs (including biosimilars) and their intricate manufacturing processes using living organisms, they are subject to batch-to-batch variability. This variation means that biosimilars cannot be identical to their reference biologic drug.

However, because of the high degree of similarity, there are no expected clinically meaningful differences in efficacy and safety between a biosimilar and its reference biologic drug.

Biosimilars and their reference biologic drugs contain well-characterized proteins as their medicinal ingredient. These are derived through modern biotechnological methods, such as the use of recombinant DNA or cell culture.

The following criteria are used to determine if products are eligible to be authorized as biosimilars:

• there is a suitable reference biologic drug for the biosimilar, which:
  • has been used in the post-market setting
  • has a substantial body of data on its safety and efficacy
• the biosimilar and reference biologic drug can be well characterized by an extensive set of sophisticated analytical methods that can detect differences in the medicinal ingredient that may impact safety and efficacy
• the biosimilar can be judged as similar to the reference biologic drug by meeting an appropriately justified set of pre-determined criteria that assess the level of structural and functional similarity between the 2 products
• the impact of any residual differences between the 2 products must be addressed to demonstrate that they are highly similar, with no expected clinically meaningful differences

These criteria are based on a comprehensive analysis of the reference biologic drug that establishes a target profile for the biosimilar.

Biosimilars versus generic drugs

Biosimilars aren't the same as generic pharmaceutical drugs. For a summary, refer to the following table (Table 1).

Generic drugs are small molecules that are chemically synthesized. They contain identical medicinal ingredients to their reference drugs.

In contrast to generics, the medicinal ingredient in a biosimilar and its reference biologic drug can be shown to be highly similar, but are not identical.

Health Canada authorizes generics based on demonstrated bioequivalence with the pharmaceutical or drug. This means that there are no significant differences in the rate and extent to which the same medicinal ingredient is released in the body.

Authorizing a biosimilar requires more studies than authorizing a generic. These studies must demonstrate that the biosimilar is highly similar to its reference biologic drug by:

• including analyses comparing the physicochemical, structural and functional properties of the biosimilar and reference biologic drug
• evaluating the biosimilar and the reference biologic drug under stress conditions (like heat-stress and pH stress) to confirm their degradation profiles are similar

Table 1. Comparison of biosimilar and generic drugs

Biosimilar drug	Generic drug
Derived from a biological source (human, animal, plant or microbial)	Chemically synthesized
Highly similar to the reference product	Bioequivalent to the reference product
Large, structurally complex molecules	Small molecules
Requires advanced techniques to characterize	Requires a lesser number and less advanced techniques to characterize
Authorization is based on demonstrating similarity using various studies that compare it to a reference biologic drug, including a head-to-head clinical comparative study (within a pre-established acceptable range of variability)	Authorization is based on demonstrating bioequivalence and pharmaceutical equivalence (within a pre-established acceptable range of variability)
Authorization requires a complete dataset on quality and manufacturing, as well as additional studies comparing the structure and activity to that of the reference biologic drug	Authorization requires a complete dataset on quality and manufacturing
A biosimilar can be authorized for all of the indications granted to the Canadian reference biologic drug if supported by sufficient evidence (refer to Table 2) and if intellectual property rights are respected	All indications for the reference product may be granted to the generic based on its demonstration of bioequivalence (if intellectual property rights are respected)