Biosimilars and Biologics
Biosimilars and biologics in Canada: A legal guide. Prepared in association with Fasken, a leading global law firm, this is an extract from The Pharma Legal Handbook: Canada, available to purchase here for USD 99.
1. Are biosimilar medicines considered the same as generic medicines in your country?
A biosimilar is not a generic biologic product since it is not identical to its reference product; its authorization does not constitute evidence of pharmaceutical equivalence, bioequivalence or clinical equivalence. A biosimilar is a subsequent entry version of a Canadian approved innovator biologic with demonstrated “similarity” to a reference biologic drug.
2. Are all biologic medicines, including biosimilar medicines, patentable in your country?
In Canada, subject matter patentability of biotechnological products is not specifically addressed in the law and must be approached in view of the definition of invention in the Patent Act. The Patent Act defines an invention as “any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement to any art, process, machine, manufacture or composition of matter”. In this respect, biotechnological products – and thus biosimilars – can be considered as “manufacture and/or composition of matter.” Biotechnological processes and uses can also be included in the “art” category. Indeed, the Patent Office explains that biomolecules are chemical compounds, and claims to nucleic acids, polypeptides, proteins and peptides are therefore patentable. The Office has for many years granted claims to isolated DNA sequences, recombinant DNA sequences, as well as monoclonal antibodies, and continues to do so. Some of these patents have been tested in the Courts, but not as yet with respect to subject-matter patentability.
Of course, biologic drugs can only be patented if they are new, non-obvious, and useful. This requirement makes it more difficult to patent biosimilars, which are a subsequent version of an existing biologic drug.
3. Is there a specific regulatory framework for the marketing authorization of biosimilar medicines in your country? If yes, what is the regulatory framework for the authorization of biosimilar medicines?
The legal framework for the approval of a biologic drug involves the same legislation and regulations as for the approval of a conventional drug. However, because of its specificities, a biologic product follows a particular path within this legal framework.
In Canada, public safety requires that the sale or advertising of a new drug be approved by the Minister of Health. In the case of a new drug, including a new biologic drug, the innovator must file a submission which contains sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug, including data from clinical trials. If the Minister is so satisfied, a marketing approval is issued.
The manufacturer of a biosimilar who wishes to obtain a marketing authorization on the basis of a comparison with an already approved biologic product (the reference biologic drug) may seek to rely on prior information regarding that biologic drug in order to present a reduced clinical and non-clinical package as part of its submission. In order to be able to do so, however, similarity between the products must be demonstrated. This is done with structural, functional and human clinical studies. In particular, there must be no clinically meaningful differences in safety and efficacy between the biosimilar and its reference product.
4. What kind of data package is needed to obtain approval for a biosimilar drug? Is this any different to the requirements for the original Biologics drug?
In addition to the standard chemistry and manufacturing data package required for all new biologic drugs, the biosimilar submission must include extensive data demonstrating its similarity to the reference biologic drug in terms of quality attributes. Such similarity may support a possible conclusion of similarity for safety and efficacy purposes.
Similarity is primarily deduced from comprehensive and well-rationalized quality studies, including extensive side-by-side characterization studies. The extent of the necessary studies will depend on the nature of the product, the availability of suitable analytical techniques, the relationship between quality attributes and safety and efficacy, and the differences between the expression systems used to manufacture the products. When considering the similarity of products, physicochemical properties, biological activity, immunochemical properties, impurities, and stability must be evaluated.
If the biosimilar and its reference product are highly similar, then it might be possible to predict that any difference in quality attributes should have no adverse impact upon the safety and efficacy of the biosimilar. It might also be possible for the manufacturer to rely on the non-clinical and clinical data previously generated with respect to the reference biologic drug. The degree of similarity at the quality level will determine the scope and the breadth of the required clinical and non-clinical data.
Insofar as clinical studies are concerned, they involve pharmacokinetic and pharmacodynamic studies. A comparative clinical trial is done in most cases in order to definitively rule out any meaningful clinical differences between the biosimilar and the reference biologic product. Safety and immunogenicity must also be compared. In vivo non-clinical studies may not be necessary where structural, functional, and extensive in vitro mechanistic studies indicate similarity.
Of course, if similarity has not been established, the product cannot be considered a biosimilar.
5. What are the requirements for the choice of the reference comparator product?
The reference product to which a biosimilar is compared must be a biologic drug that was authorized on the basis of a complete data package (which includes quality, non-clinical, and clinical information). The reference biologic drug should have accumulated adequate safety, efficacy and effectiveness data in the post-market setting. Another biosimilar can never be used as a reference product.
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
In appropriate circumstances, a biologic drug that is authorized for sale in another jurisdiction may be used as a reference product. The non-Canadian reference biologic drug should be marketed in a jurisdiction that has standards similar to Canada.
7. How are the prices of biosimilar medicines regulated? Is this any different from the requirements for the original Biologics drug?
The Patented Medicine Prices Review Board (“PMPRB”) regulates the cost of patented medicines in Canada, including biologics and biosimilars, where applicable. The PMPRB sets the maximum price for which a patented drug may be sold in Canada.
The pan-Canadian Pharmaceutical Alliance (“pCPA”), a coalition of public drug plan representatives negotiates formulary listing and funding terms of biologics and biosimilars on behalf of the provincial, territorial and federal ministries of health. While the pCPA does not have a comprehensive Canadian regulatory framework for pricing, it has released several policy direction documents, including Principles on Subsequent Entry Biologics, which expressed support for long-term cost reductions for biosimilars and Biologics Policy Directions and pCPA Negotiations, which recommended policies for encouraging competition and uptake of biosimilars.
8. What is the reimbursement policy for biosimilar medicine? Is this any different from the requirements for the original Biologic drug?
Similar to other drugs, the reimbursement criteria for biosimilar drugs are determined by provincial and territorial public drug plans and cancer agencies. These criteria are based on recommendations given by the Canadian health technology agencies: the Canadian Agency for Drugs and Technologies in Health (“CADTH”) and the Quebec Institut national d’excellence en santé et services sociaux (“INESSS”). As mentioned above, the pCPA conducts joint federal, provincial, territorial price negotiations for public plans. If negotiation is successful, the individual provinces may decide to reimburse the drug.
Additionally, at the provincial level, governments are beginning to limit reimbursement of biologics once there is a biosimilar on the market, e.g. for new patients and/or certain indications.
In fact, the government of British Columbia introduced a biosimilar initiative in May 2019 in which the provincial public drug plan will only cover the biosimilar versions of specific drugs for affected indications for both new and existing patients as of November 2019, unless patients are eligible for a discretionary exemption for medical reasons.
Private insurers across Canada are generally able to choose their own approach to reimbursing biosimilars but in some provinces, including, e.g. Quebec, they must offer at minimum the coverage provided by the public plan.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
Biosimilars have certainly created competition for originator reference products, largely due to the fact that they are less expensive and in light of the reimbursement policies discussed above. The pCPA has also stated that offers for biologic drugs for which biosimilars are reimbursed will not be considered for negotiation unless they offer includes a transparent list price reduction, indicating a trend towards favouring biosimilars through reimbursement policies. Nonetheless, according to the PMPRB, Canadian rebates on biosimilars as compared to the reference drug price are more modest than in other OECD countries.
10. What is the legal framework for biosimilar medicines prescribing (clinical decision maker) and dispensing (pharmacy level, hospital or retail)? Is this any different to the requirements for the original
There is no particular legal framework for biosimilar prescribing. Both physicians and pharmacists must respect the applicable provincial laws governing these professions.
Physicians have discretion to prescribe the biologic or biosimilar versions, where applicable. Nonetheless, and insofar as Health Canada’s authorization of a biosimilar is not a declaration of interchangeability, pharmacists are not permitted to switch patients from a biologic and dispense the biosimilar versions; rather the biosimilar must be specifically prescribed by the patient’s physician.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
The authority to declare two products interchangeable and thus substitutable at the pharmacy level rests with each province and territory according to its own rules and regulations. As previously stated, an authorization by Health Canada does not constitute a declaration of equivalence to the reference biologic.
In the case of a one-time change from a reference biologic drug to a biosimilar, Health Canada recommends that such a decision be made by the treating physician in consultation with the patient. Pharmacists are not allowed to switch patients from biologics to the biosimilar versions; rather the biosimilar must be specifically prescribed by the patient’s physician.
12. What are the post – authorisation requirements (including pharmacovigilance, risk management plans, post-approval studies) for biosimilar medicines? Is this any different to the requirements for
the original Biologics drug?
Health Canada monitors the safety of all drugs on the market, including biosimilars. It conducts market surveillance, monitors adverse reaction reports, investigates complaints and problem reports. Manufacturers must set up systems to monitor reported side effects, report any new information about serious side effects, notify Health Canada about studies containing new safety information and request authorization for any major changes to the manufacturing process, dose regimen or recommended uses of the drug.
13. Are there specific policies and requirements for labelling biosimilar medicines in the event of second medical use patents? Is this any different from the requirements for the original Biologic drug?
Like their biologic counterparts, biosimilar manufacturers must follow Health Canada labelling requirements, including if there are any new indications for the product. Manufacturers must also monitor any product class type-specific safety information that indicates a need for changes to the labelling of their specific biosimilar drug.
More generally, the product monograph for a biosimilar should include the following information:
- A statement indicating that the product is a biosimilar to the reference biologic drug;
- A statement that indications have been granted on the basis of similarity between the biosimilar and the reference biologic drug;
- Comparative data generated by the biosimilar sponsor on which the decision for market authorization was made summarized in a tabular format;
- Relevant safety and efficacy information from the product monograph of the biologic drug authorized in Canada to which a reference is made, including warnings and precautions, Adverse Drug Reactions/Adverse Drug Effects and key post-market safety information for all indications that are authorized for the biosimilar.
There should be no claims for bioequivalence or clinical equivalence between the biosimilar and the reference biologic drug.
14. Have there been any significant legal/judicial developments in relation to biosimilars in your country? (Including but not limited to IP, procurement, competition, misleading information campaign, access to reference comparator product)
There have been few judicial pronouncements on patents involving biologic drugs or biosimilars in Canada, although many cases are presently making their way through the Courts.
In 2019, the Quebec Court of Appeal rendered an important judgment quashing the Minister of Health’s decision to remove Remicade from the drug formulary list upon listing a biosimilar version; breaking with usual practice by the courts to defer to ministerial decisions. The Court’s main basis for reversing the decision was that the Minister had not followed the principles of procedural fairness in his relations with Janssen.
15. Are there proposals for reform or significant change to the legal, regulatory, procurement of biosimilars? If yes, when are they likely to come into force?
Health Canada is proposing to amend the Food and Drug Regulations to implement a licensing scheme to effectively regulate pharmaceuticals and biologics throughout their life-cycles. Specifically, the ability to place terms and conditions on product approvals will be enabled, such that information can be further gathered and other measures implemented post-market and used to adjust a licence as needed. This approach will create better alignment with international jurisdictions, such as the U.S. and the European Union. The Department intends to engage with key stakeholders throughout 2020 and 2021.
Moreover, Chapter 17 of the Manual of Patent Office Practice on biotechnology and medicinal inventions will be reviewed in the future, as indicated by the Canadian Intellectual Property Office.
Finally, it remains to be seen whether other provinces will follow British Columbia’s lead and implement policies which only reimburse biosimilar drugs for certain indications.