The evolution and creation of new technologies, medications, and transformation of patient care continues to advance at an astonishing pace. With the advancement of medicine over the years we have seen how biologic drugs and treatments have transformed patient care. Biologics are therapies derived from living cells as opposed to traditional drug products which are mainly comprised of synthesized chemicals. Today, physicians use biologics in effectively treating common disorders such as diabetes, multiple sclerosis, various forms of cancer and several other diseases. Despite their effectiveness, biologics have two key drawbacks to their use, and that is their high cost, coupled with limited accessibility through provincial and territorial formularies for most patients. With the aging Canadian population, increased life span, prolonged need for continued health care and the need for more complex and expensive treatments, the increased healthcare costs are inevitable.
Although Health Canada provides approval of new medications at a federal level, the reimbursement by public insurers is governed at the provincial level. This additional level of approval adds further complexity to the use of potential life saving, yet costly therapies. Hence, geographical location of a patient across our nation can have a huge bearing on availability and access to treatments. The large cost associated with biologics is due to the intricacies related to development of biologics. As many widely used biologic therapies are reaching patent expiry, resulting in loss of exclusivity, along with the constant need for cost saving alternatives, development of biosimilars is on a rapid rise.
The slow growth of the biosimilar market in Canada is due to several issues, such as lack of clear and transparent regulatory requirements, patient preferences, reluctance of physicians and health care providers and pharmacists to readily prescribe and substitute biosimilars.
A biosimilar must show high similarity to a biologic drug that has already been authorized for sale (known as the reference biologic drug (RBD)) by Health Canada. Biosimilars are approved based on a thorough comparison to a reference drug and may only enter the Canadian market after the expiry of the reference drug patents for each indication being sought and resolution of data protection issues.(1,2)
The slow growth of the biosimilar market in Canada is due to several issues, such as lack of clear and transparent regulatory requirements, patient preferences, reluctance of physicians and health care providers and pharmacists to readily prescribe and substitute biosimilars. The difficulties being faced in developing a naming convention specific to biosimilars and the slow uptake by the provincial governments and insurers further adds to the complexity of this market. The European Union (EU) presently dominate the market with numerous biologics in use, owing to the favourable government regulations in this region. Meanwhile, in Canada and the United States (US), Health Canada and the Food and Drug Administration (FDA) respectively have been less flexible in the approval of biosimilars.
In Canada, biosimilars are regulated as new drugs under the Food and Drugs Act and the Food and Drug Regulations. Health Canada’s Biologics and Genetic Therapies Directorate (BGTD) regulates biosimilars in collaboration with the Regulatory Operations and Regions Branch (RORB) and the Marketed Health Products Directorate (MHPD). It is important to note that biosimilars are not generic biologics and many characteristics associated with the authorization process and marketed use for generic pharmaceutical drugs do not apply. In fact, biosimilars must submit a new drug submission (NDS) as biologic drugs. Authorization for marketing of a biosimilar is not a declaration of pharmaceutical equivalence, bioequivalence or clinical equivalence to the reference biologic drug. This last point may explain the hesitation in uptake of biosimilars by some patients and healthcare providers. In my opinion, biosimilars play an important role in future of medicine and further education on their role for all parties involved from agencies and governmental bodies to patients and health care providers is needed.
Today, the evaluation of each biosimilar is determined case by case, tailored to each product. Although the regulatory pathway for both biologics and biosimilars is the same and an NDS must be prepared, the difference lies in the specific data required for each submission. The focus of an NDS for a biosimilar is having adequate and well designed in-vitro (analytical characterization) and in-vivo (non-clinical) studies, with several detailed pharmacokinetic (PK) and pharmacodynamic (PD) studies. For a biosimilar submission, the need for clinical studies is often limited and 1-3 small clinical trials compromise the data showing the safety, efficacy and immunogenicity of a given product. The purpose of the clinical studies in such submissions is to show comparative safety and efficacy of the biosimilar to the reference drug, with no clinically meaningful differences between the two biologics. Since a biosimilar is very similar in structure and function to a reference biologic drug with well-established safety and efficacy in many cases, clinical studies do not need to be repeated for each indication.
Today, physicians use biologics in effectively treating common disorders such as diabetes, multiple sclerosis, various forms of cancer and several other diseases. Despite their effectiveness, biologics have two key drawbacks to their use, and that is their high cost, coupled with limited accessibility through provincial and territorial formularies for most patients.
Although a reduced non-clinical and clinical data package is required, prior to approval, the manufacturer is required to show similarity between the biosimilar and a suitable reference biologic drug using the most advanced and current technologies. The degree of similarity at the analytical level will determine the scope and extent of the non-clinical and clinical trials. This explains how the assessment of each new biosimilar product is determined case by case. In working with Health Canada, it is best for manufacturers to request meetings with the agency as early as possible and prior to initiation of the full development program. As time to market for any product is of essence, early meetings will enable the manufacturers to determine if additional studies are needed before filing the NDS.
Health Canada provides a final determination of similarity based on the entire submission, including the entire data derived from comparative structural, functional, non-clinical and clinical studies. What is unique to Health Canada is the importance given to the reference drug’s patents. The reviewers at Health Canada do not consider the patent during their review of the application, but at the same time they will not authorize a biosimilar for market release until the issues related to the reference drug’s patents have been addressed. Hence, a biosimilar NDS that may receive notice of compliance (NOC), may still not reach the market for several years if the patent issues are not resolved. The updated Health Canada guidelines (2) provide more details on requirements for a biosimilar NDS, but still several areas need to be clarified such as; requirements for selection of reference product or requirements for post approval changes. The recent CARE™ publication issued on November 2017 (3) provides an excellent tabular comparison of NDS submission requirements for a biologic vs a biosimilar, which is reproduced below.
|Regulatory Pathway||New Drug Submission (NDS)|
|Chemistry & Manufacturing (C&M) Studies||Full package||Full package|
|Extensive comparative analytical studies between biosimilar and RBD|
|Non-Clinical Study||Full data package as per ICH S6(R1)||Reduced and comparative to RBD|
|PK/PD Study||Standard PK/PD studies||Comparative PK/PD profile to RBD|
|Clinical Efficacy||Required for all indications||In most cases, comparative to RBD for at least one indication in a representative indication and sensitive population|
|*Clinical Trial Design||Superiority, non-inferiority or equivalence trial design||Equivalence trial preferred over non-inferiority design. Adequately sensitive to rule out clinically meaningful differences within predefined comparability margins|
|*Study Endpoint||Clinical outcomes or validated surrogates||Sensitive and clinically relevant|
|Efficacy/Safety||Establishing evidence of efficacy and safety/Acceptable risk and benefit profile||No meaningful difference to RBD.
Safety must be assessed in a sufficient number of patients treated for an acceptable period of time
|Immunogenicity||Acceptable immunogenicity profile||No meaningful difference to RBD|
|Post Market||Risk management plan|
On a positive note for Canadians, Health Canada accepts use of a reference product from another ICH country / jurisdiction for the full biosimilar program development, including analytical similarity, non-clinical and clinical studies. The European Medicines Agency (EMA) (4,5) and FDA’s (6) requirements are not the same, as a result the manufacturer has to invest significant time and capital to conduct the comparative testing of multiple reference products and biosimilars. The question remains if conducting several comparative tests of EU and US-sourced reference products is a way to produce a more concrete body of evidence regarding the similarity, or if this practice is only to fulfill the battle of regulatory bodies. On the road to simplifying manufacturing of biosimilars worldwide, another hurdle that must be overcome will be to unify a set of requirements regarding the sourcing of reference products for biosimilar development programs. This in turn may help in further reducing the cost of biosimilars for patients.
To obtain an update on the currently approved biosimilars you can refer to Health Canada’s list titled Drug and Health Product Submissions Under Review (SUR) which lists all new drug submissions (including biosimilars) under review and approved.(7) If a biosimilar application is approved but is on intellectual property (IP) hold, the product will not be listed as approved. By referring to the list it is evident that more applications for biosimilars are being made to Health Canada each year and the review process is certainly improving. To ensure all Canadians have full access to safe, efficacious and cost-effective medications each of us, regardless of our role in this process can support the improvement and simplification of the review, approval and reimbursement processes for new treatments, and ultimately support timely delivery of new medications to patients.
Author: Mahdis Dorkalam – President CRM Pharma Consulting Inc – providing regulatory & clinical research expertise, with a focus on the needs of the Canadian market.
All information provided is the sole opinion of the author and is for general informational purposes only. The author makes no warranties to the accuracy, completeness and reliability of statements for a particular purpose.
1. Health Canada. https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/applications-submissions/guidance-documents/fact-sheet-biosimilars.html. 2. Health Canada. https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic-therapies/applications-submissions/guidance-documents/information-submission-requirements-biosimilar-biologic-drugs-1.html.
3. S. Edwards et al. Table 1. New Drug Submission Data Requirements: Biologics Versus Biosimilars. CARE™ Primer on Biosimilars [CARE™ Publication, Online and Print – Version 1, page 4.]. November 2017.
7. Health Canada. https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/submissions-under-review.html.