Facts about biosimilars

Biologic response modifiers have transformed the lives of patients with inflammatory arthritis who need them. Today, there are several biologic originators that have lost their patents, or will lose their patents, and biologic biosimilars are coming into the market place.

A biosimilar is a biologic that has similar effectiveness, safety, immunogenicity profile and quality, and delivers the same therapeutic benefits to patients as its biologic "originator". They are typically prescribed to patients by a rheumatologist or other specialist. For example, etanercept (Brenzys®) and etanercept (Erelzi®) are biologic biosimilar versions of the biologic originator etanercept (Enbrel®); infliximab (Inflectra®) and infliximab (Renflexis®) are biologic biosimilar versions of infliximab (Remicade®).


Biosimilars are not generics of their biologic originators
Biosimilars are similar, but not the same, as their biologic originators

Due to the size, complexity and natural variability of biologic medications, and because biologic medications are made in living cells rather than with chemicals, a biosimilar and its biologic originator can be shown to be similar, but not identical.

For example, the way that etanercept or infliximab is manufactured makes it impossible to produce an exact copy of the molecule. This differs from other pill-form medications you may have taken before. Medications like methotrexate and ibuprofen are made of small chemical molecules, not proteins. When patents expire on small molecule medications and generic versions are authorized for manufacture, exact copies can be made.

Biosimilars have been approved for use in Canada since 2009, and for use in inflammatory arthritis since 2014. Seven biosimilars are currently approved by Health Canada with another 15 biosimilars expected to be launched by 2020. Since the European Union approved the first biosimilar in 2006, and in inflammatory arthritis in 2013, the EU has approved 28 biosimilars.

Based on this scientific evidence and real world data, rheumatologists across Canada are now regularly prescribing biosimilars for inflammatory arthritis patients newly initiated on infliximab and etanercept, and in full consultation with their patients, beginning to transition them from their biologic originator to its biosimilar.


Biosimilar Naming
Patient and healthcare professional groups have called for uniquely different brand naming for all biosimilars entering the Canadian market place to minimize confusion about which medication was being prescribed and filled at the pharmacy counter or infusion clinic, or taken by the patient. Unique naming is also very important when tracking adverse events at the population level.
Health Canada and the Institute for Safe Medication Practices Canada (ISMP Canada) are seeking input from healthcare providers, consumers, and other interested and affected stakeholders on different approaches to the naming of biologic drugs, including biosimilars, in Canada.
The objective of the consultation, between January 18, 2018 and February 9, 2018, is to gain insight into stakeholder views on the practical impacts of different approaches to the naming of biologic drugs and biosimilars throughout the medication-use process, including prescribing, dispensing, and adverse drug reaction reporting.

http://www.who.int/medicines/services/inn/WHO_INN_BQ_proposal_2015.pdf

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformati...

 

Biosimilars in Canada

Seven biologic biosimilars are currently approved by Health Canada: infliximab (Inflectra®), infliximab (Renflexis®), etanercept (Brenzys®), etanercept (Erelzi®); somatropin (Omnitrope®); insulin glargine (Basaglar®); and filgrastim (Grastofil®).

Numerous biosimilars are currently under development globally. Health Canada is seeing a significant increase in the number of pre-submission and pipeline meetings with biosimilar manufacturers. Health Canada expects a significant increase in submissions as patent/data protections expire in Canada.

Experts predict another 15 biosimilars are expected to be launched in Canada by 2020. 

Why have biosimilars been developed and approved?

Biologics are treatments that can help patients with serious diseases such as inflammatory arthritis. However, they are complex and can be very expensive and time consuming to develop. This can limit patients’ access to such medicines, and can make it difficult for the healthcare system to afford them.

A biologic “biosimilar” enters the market after a biologic “originator’s” patent expires, like a small molecule generic medication does when the brand name medication’s patent expires.

Like legislated generic drug savings in Canada, biosimilars have the potential to improve patient access to biologics and save public and private healthcare systems billions of dollars now and over the coming years.

A study commissioned by the Patented Medicine Prices Review Board (PMPRB) and conducted by the National Prescription Drug Utilization Information System (NPDUIS), “Potential Savings from Biosimilars in Canada”, estimated potential savings for infliximab alone in Canada could range between $91M and $514M in the third year following biosimilar entry.

As reported at a Health Canada Biosimilar Workshop on March 20, 2017: “A competitive and sustainable market for biosimilar and innovator drugs could offer many benefits to the healthcare system, including broadening access to effective biologic treatments, reducing the cost burden and enabling savings to be re-directed across all areas of healthcare including funding of new innovative therapies.”

What benefits do biosimilars provide patients and our healthcare system?

Specifically, biosimilars create three main benefits to patients, the healthcare system, and society:

  1. Savings from biosimilars use can modernize “special access criteria”. Currently, patients must try and fail treatment on older, less expensive medications. Because biosimilars are significantly less expensive, public and private drug formularies can remove the need for patients to fail on these older therapies before approving reimbursement for them;

  2. Savings from biosimilars use can be reinvested into public and private drug formulary budgets making it possible to add new innovative medications coming into the market place, and by doing so, expanding patient medication choice; and,

  3. Savings from biosimilars can be reinvested into non-medication elements of care that patients need, such as specialized nursing, counselling, physio- and occupational therapy, among other important elements of a holistic inflammatory arthritis treatment plan. 

ACE wants to know what you think about biologics?

What are your views about biologics?

Biosimilars FAQs

  What are biologics?

Today in North America, Europe, and Asia, there are more biologics – originators and biosimilars – in use to treat inflammatory arthritis than in any other disease.

Over the past 18 years, biologics have become a life-saving treatment option for inflammatory arthritis patients whose disease does not respond to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) such as hydroxychloroquine or sulfasalazine. 

Biologics are made from living organisms, such as living cells that have been modified using biotechnology. This allows these living organisms or cells to produce the active substance of the biological medicine. This active substance is then harvested from the cells. The active substance is commonly called a “protein.” Biologics made up of proteins are much larger and more complex in nature than conventional, small molecule medicines such as over-the-counter ibuprofen (e.g. Advil) or by-prescription methotrexate. Biologics are administered in two ways; by self-injection under the skin or into muscle, or by intravenous (IV) infusion into a vein in the hand, wrist or arm.

While small molecule medicines are made of pure chemical substances and their structures can be identified, most biologics are complex mixtures of proteins, sugars or nucleic acids that are more difficult to identify or characterize. Because of their complexity, biologics can be very expensive and time consuming to develop. This can limit patients’ access to such medicines and can make it difficult for the healthcare system to afford them.

  What are biosimilars?

A biosimilar is a biologic that has similar effectiveness, safety, immunogenicity profile and quality, and delivers the same therapeutic benefits to patients as its biologic “originator”. They are typically prescribed to patients by a rheumatologist. For example, etanercept (Brenzys®) and etanercept (Erelzi®) are biologic biosimilar versions of the biologic originator etanercept (Enbrel®); infliximab (Inflectra®) and infliximab (Renflexis®) are biologic biosimilar versions of infliximab (Remicade®).

Biosimilars have been approved for use in Canada since 2009 and for use in inflammatory arthritis since 2014. Seven biosimilars are currently approved by Health Canada with another 15 biosimilars expected to be launched by 2020. Since the European Union approved the first biosimilar in 2006, and in inflammatory arthritis in 2013, the EU has approved 28 biosimilars.

Biosimilars have been used for many years in other diseases, such as diabetes, growth disorders and anaemia. Due to the size, complexity and natural variability of biologic medications, and because biologic medications are made in living cells rather than with chemicals, a biosimilar and its biologic originator can be shown to be similar, but not identical.

For example, the way that etanercept is manufactured makes it impossible to produce an exact copy of the molecule. This differs from other pill-form medications you may have taken before. Medications like methotrexate and ibuprofen are made of small chemical molecules, not proteins. When patents expire on small molecule medications and generic versions are authorized for manufacture, exact copies can be made.

  What is a biologic originator (also referred to as “reference biologic” or “brand name” biologic) medication?

A biologic originator is a biologic medication authorized on the basis of a complete quality, non-clinical, and clinical data package, to which a biologic biosimilar is compared in studies to demonstrate similarity.

  Will biologic biosimilars work in the same way as the biologic originators they were compared to?

A biosimilar is a biologic that has extremely similar effectiveness, safety, immunogenicity profile and quality, and delivers the same therapeutic benefits to patients as its biologic “originator” prescribed to patients by a rheumatologist.

As with any treatment, it is important patients have a thorough conversation with their rheumatologist about all available therapeutic options, the safety, benefits and risks, and the differences between the medications, before coming to a decision.

 

  Are biologic biosimilars generic versions of their biologic originators?

When a drug patent expires, pharmaceutical companies can copy that branded drug, and sell it for significantly less as a generic. Generic medications are copies of brand-name medications, have the same active ingredient, and are the same as those brand name medications in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use.

Biosimilars, like generic medications, are lower priced versions of brand name drugs and are approved through different streamlined pathways that avoid duplicating costly clinical trials. But biosimilars are not the same as generic medicines, such as methotrexate or ibuprofen, which are not proteins so when they are manufactured, exact copies can be made. These generic drugs are small molecules that are chemically synthesized and contain identical medicinal ingredients to their brand name reference products. Biologics cannot be exactly copied. For example, the way that etanercept or infliximab is manufactured makes it impossible to produce an exact copy of the molecule.

Biosimilars are developed and manufactured following the same strict quality requirements as any other biologic, using state-of-the-art methods and manufacturing. If they meet Health Canada’s safety and efficacy requirements, biosimilars are allowed to enter the market place after a biologic originator patent expires, just like a small molecule generic medication can do when the brand name medication’s patent expires. The same way generic medications are much lower in price compared to their original versions, so too are biosimilars.

 


 

  What is immunogenicity and why is it a special concern for biologics?

The immune system has evolved to recognize foreign proteins in the body. Biologics are usually injected into the body and the immune system often reacts to them. This reaction is referred to as the immunogenicity of the product. Sometimes immunogenicity can only be detected using sophisticated laboratory tests and has no impact on the patient. In other cases, immunogenicity can impact patient safety or how well the medication works.


Additional immunogenicity data from NOR-SWITCH study, the first randomized trial of transitioning from a biologic originator to its biosimilar, was presented at EULAR 2017 by Norwegian researchers who led the NOR-SWITCH study. Results show there are no concerns about transitioning patients with rheumatoid arthritis from infliximab to its biosimilar.

  How is immunogenicity being addressed for biosimilars?

Health Canada is addressing immunogenicity as part of the comparative clinical trials required for approval of biosimilars. In addition, biosimilar manufacturers are responsible to monitor the immunogenicity potential of the biosimilar after it is on the Canadian market.

  How are biosimilars regulated?

A biologic biosimilar enters the market after a biologic originator patent expires, just like a small molecule generic medication enters the market when the brand name medication’s patent expires. And just the way generic medications are much lower in price compared to their original versions, so too are biosimilars.

Biosimilars have their own Health Canada review pathway, as do biologic originators (“reference product”). However, Health Canada does not require all studies of the biologic originator to be repeated with the biosimilar medicine. Because the safety and effectiveness of the biologic originator are already well known, if the biosimilar medicine is very similar in structure and has the same biological activity, not all clinical studies need to be repeated. Instead, studies aim to show that there are no clinically meaningful differences between the biosimilar and the biologic originator (i.e. to demonstrate biosimilarity).

To be granted regulatory approval from Health Canada, the biosimilar dosage form(s), strength(s), and route(s) of administration must be the same as that of the biologic originator. Further, the active substances (medicinal ingredients) of the biosimilar and the biologic originator must be shown to be similar.

  What is interchangeability or automatic substitution?

In Canada, interchangeability often refers to the ability for a patient to be changed from one drug to another equivalent drug by a pharmacist, without the intervention of the doctor who wrote the prescription when it has been deemed interchangeable by a Provincial or Territorial regulatory body. For instance, this is a common practice for drugs that are off patent and have been deemed interchangeable with their generic equivalent.

For example, say a patient self-administers a biologic medication by injection to treat their rheumatoid arthritis. To receive the biosimilar instead of the reference product, the patient needs a prescription from a rheumatologist written specifically for that biosimilar. However, once a product is approved by Health Canada as interchangeable, the patient may be able to take a prescription for the reference product to the pharmacy and, depending on the Province or Territory, the pharmacist could substitute the interchangeable product for the reference product without consulting the rheumatologist. 

At present and as it relates to biosimilars, Health Canada has declared biosimilars not to be interchangeable with their biologic originator. Health Canada's authorization of a biosimilar is independent of provincial, territorial, or private drug plan decisions regarding its formulary listing and reimbursement or any decision as to interchangeability between these drugs. According to the new guidance from Health Canada, interchangeability decisions rest with provincial or territorial governments. They also regulate pharmacy substitution practices.

  What is therapeutic substitution?

Therapeutic substitution, also referred to as “drug switching” or “therapeutic interchange”, is the practice of replacing the prescribed medication with a chemically different medication in the same class that is expected to have the same clinical effect. Therapeutic substitution usually occurs when the prescribed medication is substituted at the pharmacy counter with another due to cost differences.

  What does “switching” or “transitioning” mean?

“Switching” or “transitioning” means a patient is moved from one medication to another. In the case of biosimilars, there are two types of transitions:

“Medical transition” occurs in the case of a patient not doing well on their current biologic originator or biosimilar of choice, who is transitioned to another biologic originator or biosimilar, with a different molecular action, based on a decision by the patient and their rheumatologist, in order to regain maximum disease control.

“Policy transition” (“non-medical switching”) occurs when a public or private drug plan’s reimbursement policy necessitate patients move from their current biologic originator to its biologic biosimilar, usually because it is significantly less expensive. Policy transition is not medically related.

Health Canada’s position on transitioning

Health Canada considers well-controlled switches from reference biologic drug to biosimilar in an approved indication to be acceptable. Health Canada recommends that a decision to switch a patient being treated with a reference biologic drug to a biosimilar, or between any biologics, be made by the treating physician in consultation with the patient and take into account any policies of the relevant jurisdiction.

What is the NOCEBO effect?

Transitioning patients from biologic originators to biosimilars is associated with the potential for a “nocebo” effect, a phenomenon that occurs when a patient’s negative expectation causes a treatment to have a more negative effect than it otherwise would—essentially, the opposite of the placebo effect.

The way in which rheumatologists and other healthcare providers communicate with patients about transitioning to a biosimilar is key to preventing the nocebo effect. Patients should be informed about the transition well in advance, and the availability of research-based information is important for patient understanding and empowerment. Finally, an appointment with a rheumatologist to discuss biosimilar transitioning should ideally allow enough time with the patient to understand the concept of biosimilars and transitioning and to address any concerns properly.

  What is extrapolation?

Because of the way biosimilars are developed, it is not always necessary to carry out clinical studies with the biosimilar in all the diseases for which the originator has been shown to work. Instead, it may be possible to extend safety and efficacy data from studies in one disease to cover others. This is known as extrapolation.

An indication is the use of a drug to treat a disease or medical condition. Many biologics (originators and biosimilars) are approved to treat more than one “indication” (disease or medical condition). The term extrapolation is often used to refer to Health Canada’s approval of a biosimilar for indications where clinical studies were not done. Because a biosimilar is very similar in structure and function to a biologic originator with proven safety and efficacy, clinical studies do not need to be repeated for each indication.

Instead, Health Canada may approve a biosimilar for use in more than one indication because of the similarity between the biosimilar and the biologic originator. Patients and physicians can have confidence in the use of a biosimilar in each indication approved by Health Canada. 

For example, extrapolation of the safety and efficacy results from a plaque psoriasis study that demonstrated the biosimilarity of the second etancercept biosimilar Erelzi to Enbrel (biologic originator), Health Canada approved Erelzi for three indications: rheumatoid arthritis, ankylosing spondylitis, and juvenile idiopathic arthritis.

Biosimilars can receive all indications (diseases/conditions) held by the biologic originator based on the “totality of evidence” obtained from all comparative analyses between the biosimilar and biologic originator.

The indications approved for a particular biosimilar depend on the following factors:

• Indications may be patented at different times. Indications still under patent and data protection cannot be approved.

• The biosimilar manufacturer chooses which indications they wish to seek for the product. Health Canada does not force a manufacturer to apply for indications that the manufacturer does not wish to have; and,

• Health Canada may decide not to approve a biosimilar for a certain indication based on scientific and benefit/risk-based considerations.

Questions about biosimilars research? Let us find the answers for you.

As biosimilars research data continues to be published and policies regulating them evolve, ACE continues to provide information for the arthritis community. As part of that commitment, we encourage you to send us questions. We will provide answers to you and add that content to our website. That’s what the Biosim•Exchange is all about.