ClINICAl CoNSIDERATIoNS FoR THE AUTHoRIzATIoN oF bIoSIMIlAR bIoloGIC DRUGS IN CANADA

A summary of the pathway to authorization for biosimilars in Canada

biologic medicines have been invaluable in the treatment of diseases ranging from cancer to autoimmune disease. The expiry of patents for many successful biologic medicines has fostered a high degree of interest in the development of subsequent entry versions, known as biosimilar biologic drugs or, simply, biosimilars. Biosimilars have the potential to increase competition and decrease the substantial costs often associated with biologic treatment.

In 2013, data published regarding the number of biosimilars in development signaled a high level of activity in this area. For example, over 40 programs were reported to be underway for biosimilar versions to three of the most successful biologics: the TNF inhibitors known as Humira, Enbrel, and Remicade[1]. Since then, a number of biosimilars have been approved and have come to market in Canada. This article is intended to provide a summary of the pathway to authorization for biosimilars in Canada with a focus on clinical aspects as outlined within Health Canada’s recently updated guidance document: Information and Submission Requirements for Biosimilar Biologic Drugs.[2]

Biologics are structurally complex and more difficult to replicate than small molecule pharmaceuticals. This is partially due to their large size, in comparison to pharmaceuticals, but also due to their production, which is accomplished by harnessing the productive capabilities of living cells. Due to the complexity of both the product and the manufacturing process, it is not possible to make an exact copy of a biologic product, and therefore the regulations that specify the requirements for demonstrating that a generic small molecule drug is pharmaceutically equivalent to its reference product do not apply. To address this, and to provide a framework for the authorization of biosimilars, Health Canada has published guidance on the information required to support submissions for biosimilar biologic drugs.

Health Canada’s guidance, originally published in 2010 and revised in 2016, provides recommendations to guide sponsors through the development of a biosimilar. Importantly, a biosimilar submission must make reference to a product that is currently authorized for sale in Canada. It is acceptable for sponsors to compare to reference product sourced from another jurisdiction, so long as the product can be justified to be a reasonable surrogate for the product that is authorized in Canada. Following the guidance should allow the sponsors of biosimilars to fulfill the requirements of the Food and Drugs Act and regulations that apply to all new drugs.

Importantly, the guidance emphasizes the need for extensive side-by-side chemistry and manufacturing comparisons. By laying the foundation for the demonstration of similarity, this extensive comparative characterization of critical quality attributes, including assessments of biological function, facilitates a reduced clinical data package. Clinical components, discussed below, are required to address the residual uncertainty that exists due to the fact that minor differences will always exist between a biosimilar

Biosimilars have the potential to increase competition and decrease the substantial costs often associated with biologic treatment.

and its reference biologic drug, and evidence should be provided that these differences are unlikely to impact clinical outcomes. When taken together, demonstrations of similarity in each of these aspects (chemistry and manufacturing, biological function, clinical outcomes) establish a scientific bridge that allows the biosimilar to draw on the established safety and efficacy of the reference. As follows, a biosimilar is eligible to seek authorization for each indication held by the Canadian version of the reference biologic drug with the expectation that clinical outcomes will not differ meaningfully, whether a patient receives the biosimilar or its reference.

In general, the clinical aspects recommended supporting a biosimilar submission include side-by-side investigations of pharmacokinetics/pharmacodynamics (PK/PD), safety and efficacy, and immunogenicity. In certain circumstances a side-by-side PD assessment may replace a comparative investigation of efficacy; however, this requires the existence of a PD marker that is reasonably predictive of efficacy. In either case, the safety of the biosimilar should be characterized. The purpose of these studies is to exclude clinically meaningful differences in PK/PD, safety, efficacy and immunogenicity that would refute the biosimilarity of the product.

Comparative PK/PD studies intended to support a biosimilar submission should be conducted in healthy volunteers, when appropriate, since this population is considered homogenous and is a sensitive model in which to detect product specific differences. Some considerations should be taken into account when designing comparative PK studies to support a biosimilar submission. For example, biologics often have long half-lives, PK may be nonlinear and influenced by targetmediated drug disposition, and the presence of endogenous protein may interfere with detection methods. All of these factors may influence the type (e.g. cross-over vs. parallel group), size and duration of study that is necessary to provide evidence of similarity in PK. When possible, PD should be investigated within the comparative PK study; however, it is recognized that for many biologics, valid PD markers do not exist. In the absence of a valid PD marker, evidence of similar efficacy is needed to establish that the biosimilar does not produce outcomes that are meaningfully different from the reference.

At least one well designed, randomized, controlled safety and efficacy study is usually recommended to support a biosimilar submission. In most cases, the efficacy of the biosimilar should be demonstrated to be statistically equivalent to the reference product, based on pre-defined margins. Margins should be established based on historical information available for the reference product and should exclude differences that would be considered clinically meaningful. The study population and study outcomes selected to compare the biosimilar and reference should be considered sufficiently sensitive to detect differences between products, should they exist. Factors that may affect the sensitivity of the clinical trial include the expected magnitude of effect (based on historical efficacy information for the reference), the homogeneity of the population, the use of concomitant medications, and the duration of treatment and follow-up. Sponsors are encouraged to demonstrate equivalent efficacy in the most sensitive setting possible as this provides the most robust demonstration of similarity. Safety assessments should be included in the study and should involve descriptive comparisons of adverse events occurring after the initiation of treatment. Observed safety signals should also be compared against the known safety profile of the reference product to determine whether new signals have been identified. It is recognized that this type of assessment will often be incapable of detecting differences in the incidence or severity of events that may be rare to begin with. Due to this, appropriate risk management plans and post-marketing surveillance are critical in strengthening the safety database for biosimilars. This approach to post-market monitoring is similar to that in place for all new biologic medicines.

Finally, immunogenicity is a key consideration in the development of biosimilars and should be explored within the comparative safety and efficacy study(ies). This is for several reasons, chief among them being that the development of immunogenicity can have unwanted consequences ranging from severe adverse reactions to neutralization of the biologic, which can lead to reduced efficacy. Furthermore, the immune system is considered highly sensitive, with even minor molecular differences having the potential to elicit a significant immune response. Therefore, demonstrated similarity in the incidence, magnitude, and persistence of the immune response, observed in an appropriately sensitive population, provides additional evidence that the biosimilar and the reference can be expected to produce comparable outcomes. Importantly, consideration must be given to the assay(s) used to assess the immunogenicity of the biosimilar and reference biologic drugs. These assays should be validated, sensitive and sufficiently drug-tolerant so as to allow for a robust assessment of immunogenicity.

In conclusion, Health Canada’s guidance on biosimilar biologic drugs specifies rigorous comparisons of chemistry and manufacturing attributes, nonclinical aspects, as well as clinical studies comparing the PK/PD, safety and efficacy, and immunogenicity of a biosimilar biologic drug to its reference. When taken as a whole, evidence of similarity in each of these aspects allows for a conclusion of biosimilarity, meaning that, in any given setting, the biosimilar is expected to produce clinical outcomes that are not meaningfully different from those expected with the reference biologic drug.

For more information regarding the development of biosimilar biologic drugs for the Canadian market, please consult the guidance document: Information and Submission Requirements for Biosimilar Biologic Drugs.

References

1. Rader RA. 2013. An Analysis of the US

Biosimilars Development Pipeline and

Likely Market Evolution. BioProc. Int. 11(6): S16 – 23. 2. Health Canada. 2016. Guidance Document: Information and Submission

Requirements for Biosimilar Biologic

Drugs.

Bradley J. Scott, is a senior clinical evaluator, for the Biologics and Genetic Therapies Directorate, Health Products and Food Branch at Health Canada.

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