Handbook for health care professionals on biosimilar biologic drugs: Data requirements, labelling and indications

On this page

• Data requirements for authorization
• Labelling: product monographs for biosimilars
• How we authorize specific indications

Data requirements for authorization

In Canada, biosimilars are regulated as new drugs under the Food and Drugs Act and the Food and Drug Regulations. Within the context of these legislative and regulatory requirements, Health Canada has developed a robust, evidence-based regulatory framework for authorizing biosimilars for sale.

Biosimilars must meet the same regulatory standards as other biologic drugs and are only authorized after a scientific evaluation by Health Canada. These rigorous standards mean that patients and health care professionals can have as much confidence in the quality, efficacy and safety of a biosimilar as with any other biologic drug.

In addition to the regulatory information required for all biologic drugs, biosimilar manufacturers must provide information to Health Canada that demonstrates the similarity of their biosimilar to the reference biologic drug. Manufacturers should use extensive comparative studies in a stepwise approach:

• beginning with physicochemical, structural and functional studies
• continuing with non-clinical and human clinical studies

Because the purpose of these studies is to demonstrate similarity, biosimilars are supported by different data than their reference biologic drugs for authorization.

For a reference biologic drug to become authorized for sale, manufacturers must demonstrate the quality, efficacy and safety of the drug. Generally, authorization of an originator drug requires stand-alone "pivotal" phase III clinical trials. These establish efficacy and safety in each disease or medical condition that the drug is intended to treat. (The data requirements for authorization are listed in Table 2.)

In contrast, to obtain authorization for sale, biosimilar manufacturers must:

• demonstrate the quality of the drug
• perform extensive comparative studies against the reference biologic drug to demonstrate high similarity in:
  • function
  • structure
  • safety
  • efficacy

Biosimilars can be authorized only with extensive side-by-side comparative quality studies. The studies compare the characteristics of the proposed biosimilar and its reference biologic drug, including:

• functional activities
• structural properties
• purity and impurity profiles
• physicochemical properties
• immunochemical properties
• product stability and degradation profiles

Structural and functional studies are generally considered more sensitive than clinical studies for detecting differences between a biosimilar and its reference biologic drug. Due to the sensitivity of these studies, they are able to identify differences at the molecular level that might affect safety and/or efficacy.

Clinical studies, where the biosimilar is compared to the reference product, are used to show that there are no clinically meaningful differences between the biosimilar and the reference biologic drug.

As all biologic drugs vary somewhat, biosimilars can exhibit minor differences to the reference biologic drug. Health Canada further evaluates the potential impact of these differences on efficacy, safety and immunogenicity (ability of a foreign substance, known as an antigen, to provoke an immune response) by assessing:

• clinical and non-clinical studies
• analyses of physicochemical, structural and functional properties

The information needed to address such minor differences should be considered on a case-by-case basis and will depend on the actual difference(s) observed. In some cases, non-clinical data (such as data from in vitro experimental models) might be generated to further investigate the observed differences and their impact on relevant experimental outcomes. A clinical trial could be requested to compare the clinical performance of the biosimilar to the reference product in a patient population.

As a rule, detailed scientific rationales should address such differences and the potential impact (or lack) on the performance of the biosimilar in each of the requested indications. Major differences between a biosimilar candidate and its reference biologic drug may prevent the product from being considered as a biosimilar.

These studies will include comparisons of the relative levels of the medicinal ingredient in the blood over a relevant period. Typically, a clinical trial comparing the biosimilar directly to its reference biologic drug is required to confirm that there are no clinically meaningful differences. These comparative clinical studies should be designed to detect potential differences between the biosimilar and its reference biologic drug.

In certain circumstances, a clinical efficacy trial may not be necessary, such as where there is a validated and sensitive pharmacodynamic (PD) endpoint. For example, euglycaemic clamp studies, which measure blood sugar control in response to insulin, would be enough to demonstrate similar efficacy between 2 insulin products. In such cases, a scientific justification is needed and safety as well as comparative immunogenicity data are still required.

Authorization of all biosimilars is based on all of the evidence given to Health Canada. This includes a complete quality data package and all of the data from the following comparative studies:

• clinical and non-clinical
• structural
• functional
• physicochemical

Although the clinical data requirements for a biosimilar are reduced in comparison to its reference biologic drug, the quality data requirements are increased. The latter data requirements are more comprehensive due to the need to perform extensive characterization studies.

We review how we regulate biosimilars on an ongoing basis in response to:

• best practices
• experience gained
• scientific evidence and advances

In summary, in order to authorize a biosimilar, Health Canada must evaluate the information provided by the manufacturer and conclude that it shows:

• the biosimilar and the reference biologic drug are highly similar and
• there are no clinically meaningful differences in efficacy, safety and immunogenicity between the biosimilar and the reference biologic drug

Case study: The authorization of Kanjinti, a biosimilar to Herceptin

Labelling: product monographs for biosimilars

A product monograph (PM) is a factual, scientific document containing pivotal information on a drug. The PM is issued when a drug is authorized.

Along with other information that may be required for optimal, safe and effective use of the drug, the PM contains the following details to inform patients, consumers and health care professionals:

• name
• therapeutic or pharmacologic classification
• properties
• indications
• dosage regimen
• information on adverse events
• actions and/or clinical pharmacology
• conditions and considerations for safe use
• plain language summary of these details

Note: Biosimilars are identified as such in the product monograph immediately before the health professional information (Part 1) in the product monograph.

A PM also includes the drug's:

• date of last revision
• date of initial approval
• summary of revisions

The PM for a biosimilar will also include:

• a statement that the product is a biosimilar to its reference biologic drug
• a statement that indication(s) have been granted on the basis of similarity between the biosimilar and the reference biologic drug
• safety information on the reference biologic drug for all indications authorized for the biosimilar

A PM cannot contain any promotional material. A PM for a biosimilar should not declare therapeutic equivalence of a biosimilar to its reference biologic drug. No information on interchangeability or switching between drugs should be included in a PM for a biosimilar.

The PM for a biosimilar must be updated whenever new information about the biosimilar or the reference biologic drug becomes available. The manufacturer can initiate these updates or Health Canada can mandate them.

For details on the requirements for preparing PMs, consult:

• Guidance document: Product monograph

Product monographs for all biosimilars authorized in Canada are available in the Drug Product Database.

More information on updating PMs is in the Access to biosimilars and communicating with patients section.

How we authorize specific indications

Once studies demonstrate similarity between the biosimilar and its reference biologic drug, Health Canada can authorize the biosimilar for some or all of the same indications as the reference biologic drug. An indication refers to the use of a drug to treat a specific disease or medical condition. Many drugs, including biosimilars, are authorized for more than 1 indication. Health Canada can only authorize indications requested by the biosimilar manufacturer.

The biosimilar manufacturer does not need to conduct comparative clinical trials in all of the indications that have been granted to the reference biologic drug. We can grant some or all indications to the biosimilar based on the previously established efficacy and safety of its reference biologic drug, the pathophysiology of disease and the mechanism of action of the drug. This concept is called extension of indications.

Patients and prescribers can have confidence in the use of a biosimilar in each indication that we authorize.

Extension of indications depends on similarity being demonstrated between the biosimilar and the reference biologic drug, using data from comparative:

• clinical and non-clinical studies
• structural and physicochemical studies
• functional studies

Where similarity has been established, we may grant indications, even though specific clinical studies with the biosimilar were not conducted for each indication.

A biosimilar sponsor can apply for the indication(s) and condition(s) of use held by the reference biologic drug authorized in Canada. However, the biosimilar manufacturer may choose not to seek all indications held by the reference biologic drug.

The indications authorized for a particular biosimilar depend on the fact that:

• indications for the reference biologic drug can be patented at different times and
• indications under intellectual property protection cannot be authorized until the protection expires

Since a biosimilar is very similar in structure and function to a reference biologic drug with well-established safety and efficacy, clinical studies do not need to be repeated for each indication.

The biosimilar manufacturer chooses the indications for which they wish to seek authorization for the product. Health Canada cannot force a manufacturer to apply for indications that the manufacturer does not wish to have in Canada. We also cannot authorize an indication that the manufacturer has not requested.

Learn more about the basis for decisions on biosimilar authorization:

• Summary basis of decision (SBD) documents and regulatory decision summaries)
• Case study: Inflectra (infliximab) for Crohn's disease and ulcerative colitis