Canadians, today, are living longer, healthier lives thanks to innovative treatments for a variety of conditions. Many of these medicines are biologics — a class of drugs made from living organisms. The ability of these medicines to precisely target pathways and cells responsible for the development of disease is revolutionizing our battle against conditions like cancer, autoimmune diseases, diabetes and other conditions. Thanks to these medicines, as well as improvements in screening and diagnostics, Canadians are living longer, healthier lives. For example, in breast cancer, the number of deaths has fallen by 44% since 1986.
While biologic medicines have provided Canadians with effective treatment options for more than 20 years, the recent introduction of biosimilars - similar but not identical versions of biologics - is changing Canada’s healthcare landscape. The complexity of discovering, manufacturing and introducing these treatments in our current regulatory and reimbursement systems has raised questions among Canadian patients, healthcare professionals, and others in the healthcare community.
As a research-based pharmaceutical company, we believe the approval of any new treatment option is a positive development for patients. Given the complexities of this topic and the variables that still need to be determined in how biosimilars will be integrated into the the Canadian healthcare system, we think it’s important to shed some light on what originator biologics and biosimilars are, how they are manufactured and how they are approved for use in patients
Today, medicines are either chemically-based or biologically derived compounds, which differ significantly in how they are made and how they work in the body.
Small, chemically manufactured molecules are made using chemical reactions between different organic and/or inorganic compounds. Small molecule medicines, such as Aspirin (acetylsalicylic acid), make up over 90% of the medicines available in the Canadian market.1 Because of their size, small molecules can be processed into tablets or capsules that dissolve and are absorbed into the bloodstream. It is also relatively simple to make an exact copy of these medicines, known as a “generic” equivalent.
Biologic medicines, on the other hand, are proteins made by using living organisms, such as bacteria, yeast, mammalian cells, or tissue and are thousands of times larger and more complex to develop than small molecules. In fact, biologic medicines are often 200 to 1,000 times the size of a small molecule medicine.1 Because they are significantly larger and more difficult for the body to absorb, biologics are given through subcutaneous injection or they are “infused,” meaning they're given intravenously (IV) in a clinic or hospital setting. Further, the body’s immune system is designed to recognize foreign proteins and as a result people often have reactions to these medicines. These immune reactions are referred to as immunogenicity.
The complexity of the science that supports the development of biologics inherently affects the complexity of their manufacturing process. Specifically, the fact that biologics are produced in living cells makes it that much more complex for those trying to understand how a biologic medicine is produced. For example, no two living systems are exactly the same so there are differences that impact biologic manufacturing between these cell lines. They are extremely sensitive to external conditions like temperature, pressure and other variables, and different process conditions can result in different product characteristics.
As you can see in this video from the Discovery Channel’s leading documentary series, How It’s Made, manufacturing a biologic medicine is not a simple task.
Biosimilars are not the same as generic drugs for small molecules. Due to the size, complexity and natural variability of biologic medicines, and because they are made in living cells rather than with chemicals, an exact copy is impossible to make. Biosimilar manufacturers begin with a different living organism and must develop their own manufacturing process independently, which means a biosimilar and its reference biologic drug can be shown to be similar, but not identical.
Like all medicines, biosimilars must go through an approval process to establish their safety and efficacy. Companies that manufacture biosimilar medicines must provide information to Health Canada comparing the biosimilar with the original medicine, known as a reference biologic drug. Because the purpose is to demonstrate similarity, the type of data required to support a biosimilar approval is different from that of an originator biologic drug. Health Canada evaluates all of the information provided to confirm ‘similarity’ and that no clinically meaningful differences in safety and efficacy are apparent. That being said, because immunogenicity (a patient’s immune response) can impact patient safety or how well the medicine works, it’s important that the reference biologic and the biosimilar can be uniquely identified and monitored after approval.
Many medicines are used in more than one disease type or “indication.” For example, a medicine may be approved for use in different types of cancers. Biologic medicines must undergo extensive clinical studies for each of these indications to ensure that they are safe and that the specific patient population will benefit from using this medicine.
Because a biosimilar is similar in structure and function to the reference biologic drug, which has well-established safety and efficacy data, clinical studies do not need to be repeated for each indication. In some cases, Health Canada may authorize a biosimilar for use in more than one indication based on data from just one clinical study.
While we know how biosimilars are approved in Canada, the process by which biosimilars will be funded and used in clinical practice has yet to be determined. Canada’s healthcare system is complex — while Health Canada determines which pharmaceutical products and medical devices are approved for use in Canada, it is up to each province and territory to determine what treatments are funded in their jurisdiction.
There are a number of key considerations when looking at how biologics and biosimilars will co-exist within our healthcare system:
Can a patient already being treated with a reference biologic drug be switched to a biosimilar?
Switching generally refers to a one-time change from a reference biologic medicine to a biosimilar. In some disease areas, such as cancer, there is limited data available about switching patients from a reference biologic to a biosimilar, which should be further studied through clinical trials to ensure there is no impact on the patient. Health Canada recommends that the decision to switch a patient currently on treatment should be made by the treating physician in consultation with the patient, taking into account available clinical evidence and any policies of the patient’s jurisdiction (i.e., province and/or territory of residence).
Will biosimilars and biologics be interchangeable?
Traditionally, patients who are prescribed a medicine that is interchangeable are able to be switched from one medicine to another equivalent medicine by a pharmacist, without speaking with the doctor who wrote the prescription. Due to the complexity of biologics, biosimilars are not the same as generics. Health Canada's authorization of a biosimilar is not a declaration of equivalence to the reference biologic drug. In Canada, the authority to declare products interchangeable rests with each province and territory, according to its own rules and regulations. As with switching, there is limited data available on interchangeability, which will need to be evaluated by provincial health authorities. However, in the United States, the Food and Drug Administration (FDA) is developing guidance on the study requirements for a biosimilar to be considered interchangeable with the reference biologic.
How are biosimilars uniquely identified?2
Since biosimilars are not identical to their reference biologic, a distinguishable name is important to monitor and trace products, particularly to report any side effects patients may experience. Health Canada recently provided a policy statement indicating “Both the brand name and non-proprietary name should be used throughout the medication use process so that biologics that share the same non-proprietary name can be distinguished by their unique brand names.” They have also indicated that further guidance will be forthcoming. Once this happens, electronic medical systems in hospitals, pharmacies and private clinics may need to be updated. Health Canada is also working on a reporting system to encourage including both the brand name and the non-proprietary name in side effect reporting. Specific timelines for roll-out of this guidance have not been established, so stakeholders aren’t yet able to prepare.
Although there are many variables that have yet to be determined by the relevant government stakeholders, the introduction of biosimilars is a positive development for patients and the Canadian healthcare system. An open, competitive marketplace is critical to long-term sustainability, and having multiple suppliers mitigates the impact on patients in the case of a product shortage. It is important that both innovator biologics and biosimilars co-exist within the marketplace and that physicians and patients are aware of all treatment options available. A physician’s ability to prescribe a medicine that is best suited for their patient, and a patient’s ability to engage in a meaningful discussion about their treatment choice, is critical to the future of our healthcare system.
September 22, 2018, revised March 4, 2019
1. This statistic was referenced in a 2016 Fraser Institute report on biologics. Due to Canadian regulations we are unable to link to the report directly.
2. This section was revised March 2019 to reflect new Health Canada guidance.