A review of biosimilar in regulations and potential impact: Hong Kong perspectives

Introduction

Biopharmaceuticals, including well-known vaccines and gene therapy, have been thought to be one of the game changers in the healthcare system. Monoclonal antibodies and recombinant proteins, or simply biologics, are of no exception. There are a number of barriers for the advancement of biopharmaceuticals development ranging from clinical studies, information technology, data science, regulatory issues, manufacturing processes, and formulation and delivery.

A Food and Drug Administration (FDA)-approved biosimilar is highly similar to and has no clinically meaningful differences in terms of purity, safety, and potency from an already FDA-approved biological product, called the reference product¹. The approval of biosimilars enables competition, increases consumer choices, and supports greater access to important therapies². Biopharmaceutics have been a challenging business model of drug development and healthcare delivery model, but it is estimated that the biosimilar could accelerate the growth of the pharmaceutical industry³.

Biosimilars are distinctive from generic products in a few ways. First of all, manufacturing of biosimilars involved biotechnology, and the size of the products were much bigger with higher complexity in structure than generic drugs^1,4. The current article aims to evaluate the regulations of biosimilars in both Hong Kong and overseas countries, as well as the potential impact on both healthcare systems and patients upon the introduction of a biosimilar.

Regulations of biosimilars

US and European countries

The regulatory pathway for the development of a biosimilar differs significantly from that of the biologic innovator. Such a paradigm shift is required because the major goal of the development of the biologic innovator was to determine efficacy, whereas the development of a biosimilar is focused on bridging to the clinical experience of the originator with totality of evidence, including analytical, non-clinical, pharmacokinetic/pharmacodynamic, and clinical data^1,4.

From the analytical perspective, a biosimilar should have (i) identical amino acid sequence (or primary structure); (ii) indistinguishable folding in both secondary, tertiary, and quaternary structure; (iii) glycosylation and related substances; and (iv) identical biological assays such as receptor binding, Complement-Dependent Cytotoxicity (CDC) assays, and NK cell Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) assays, to the originator^1,4. However, despite strict controls, slight variations were still possible during post-translational modifications and could have a significant impact on effector function and immunogenicity. For example, the afucosylated Fc fragments of the FcγRIIIa could lead to a 100-fold higher affinity than the fucosylated version⁵. As a result, biosimilarity has to be confirmed both pre-clinically and clinically within a strict regulatory pathway.

From the clinical data perspective, according to the guidelines from European Medicines Agency (EMA) guideline, the biosimilar to be registered has to undergo pharmacokinetic/pharmacodynamic and efficacy and safety studies⁴. The aims of the clinical trials required were to demonstrate comparable pharmacokinetic data in sensitive and homogenous populations, using an equivalence study design to show efficacy in randomized comparable parallel double blind studies and to reveal a comparable safety profile compared to the original. However, the statistic confidence interval limits may vary from country to country. For instance, FDA defines 12% of interval limits as “no clinically meaningful differences”, while EMA adopts 15% of the margin^2,4. Extrapolation of indications from reference products to biosimilar products would only be approved based on the totality of evidence.

Concerning the switching of biosimilar products, including interchangeability and substitution, the current evidence was neither designed nor powered to support non-inferiority or equivalence of switching. This led to physicians’ and pharmacists’ uncertainty with the use of biosimilar products. As a result, the possibility of switching was regulated in each country in Europe, and there is no FDA-approved interchangeable biosimilar as of today. Therefore, it is important to improve the pharmacovigilance system to complement clinical trials for immunogenicity detection. In addition, patient motivation is also important in disease management.

Hong Kong

With the consultations and comments from various stakeholders, together with the “Guideline on Evaluation of Similar Biopharmaceutic Products” from the World Health Organization, a local guidance note for registration of biosimilar products was developed and became effective from January 1, 2016⁶. Similar to the regulatory requirements overseas, quality, non-clinical, and clinical documents and immunogenicity studies are also required for the registration of a biosimilar in Hong Kong.

A full quality dossier with information on extensive characterization studies as well as the development, manufacturing process, and quality control of both the active substance and the finished product should be submitted during the registration process. Any observed differences found in the comparability exercise between the biosimilar and reference products on both the active substances and the finished product needs to be justified⁶.

Mandatory non-clinical studies include in vitro studies demonstrating comparability in reactivity of the products, taking receptor-binding studies or cell-based assays as an example. Routine toxicological studies such as safety pharmacology, reproductive toxicology, mutagenicity, and carcinogenicity are generally not required unless triggered by differences identified at the quality level and/or the results of the repeat dose toxicity studies or known toxicological properties of the biosimilar or reference products.

Pharmacokinetic (PK), pharmacodynamics (PD), and clinical efficacy and safety comparative studies are considered as clinical data for the registration of biosimilars. If the reference product has more than one proposed indication, the efficacy and safety of the biosimilar product for each proposed indication should be demonstrated separately. Extrapolation of clinical data to other indications of the reference product could be acceptable only when comparability has been demonstrated thoroughly in one indication⁶.

Immunogenicity data of the biosimilar product should include (i) antibody testing strategy; (ii) characterization of the observed immune response; (iii) evaluation of the relationship between antibody formation and PK or PD profile relevant for clinical safety and efficacy in all aspects; and (iv) consideration on the risk of immunogenicity in different therapeutic indications or patient populations separately⁶. Immunogenicity should be investigated in the patient population with the highest risk of an immune response and immune-related adverse events for extrapolation of the indications.

Another key registration requirement of a biosimilar in Hong Kong was the need of marketing authorization in at least one of the following agencies: FDA of the US, EMA, Ministry of Health, Labour and Welfare of Japan, Therapeutic Goods Administration of Australia, and Health Canada. Further to the marketing authorization, the reference products should have been registered in Hong Kong for over 8 years⁶.

In addition to the documentation requirements, pharmacovigilance programs, including reporting of local suspected serious or unexpected adverse drug reactions, submission of periodic safety update reports (PSURs), risk management plan, risk evaluation and mitigation strategy, and preparation of education materials for healthcare professionals and patients were also mandatory for the registration. Apart from the labeling requirements for chemical pharmaceutical products, specific labeling information were also required for biosimilar products, including a statement of the nature as a biosimilar product and the risk of substitution of reference products. On the contrary, any claims for bioequivalence or clinical equivalence is prohibited. In fact, the Department of Health did not endorse the substitution of reference products with biosimilar products. The suitability of substitution relies heavily on the professional judgment of the healthcare professionals⁶.

Impact of biosimilars

Even with the inherent constraints of biosimilar substitution, introduction of biosimilars in the Hong Kong market is expected to bring the impact on various aspects, including patient, public health system, private healthcare, and society.

Healthcare perspective

According to the local consumption data, more than 8,000 patients were prescribed with biologic for treatment of rheumatology-related disease in public hospitals in Hong Kong from 2006 to 2016. More than 60% and 40% were prescribed with rituximab and tumor necrosis factor inhibitors (TNFi), respectively. As a statutory organization being heavily subsidized by the government, Hospital Authority would save HKD 230 million per year with the introduction of biosimilar⁷.

The savings of biosimilar products would probably be overestimated due to the high investment required for research and development and manufacturing. In South Korea, price reduction is mandatory upon expiration of patent and is capped at 80% of the price during the on-patent period, comparing to chemical generic products, the maximum price is 53.55% of the on-patent originators⁸. Similarly in Taiwan, the reimbursement price of biosimilar is based on the lowest price of the following calculation (i) 85% of the listed originator price; or (ii) 85% of the median price of the originator in 10 reference countries. Hence, the cost-saving effect may not be as drastic as expected⁹.

In addition, the increased accessibility to biologic agents may incur additional costs of care ranging from administration costs to additional monitoring of adverse drug reactions, and these costs are independent to the drug budget of Hospital Authority. A local specific budget impact analysis would possibly be needed to assess the drug costs saved and the additional number of patients that could be treated using these savings.

Patients’ perspective

With the reduced costs after the introduction of biosimilar, it is inevitable that the accessibility to biologic therapy would be enhanced and more patients could be treated with the less expensive biologics. However, uncertainties exist for the application of a biosimilar in Hong Kong. Potential immunogenicity and unclear long-term adverse effects of biosimilars aside, the temptation to use unregistered biosimilars is prominent given the price differences. Use of unregistered drugs demolish the monitoring from pharmacovigilance programs and renders the use of biosimilars untraceable by legal authorities. Given the previous incidence of pure red aplasia and epoetin alfa in 2001¹⁰, biosimilar should not be treated as generic and considered as interchangeable to the branded biologics.

A local survey was conducted by the Hong Kong Alliance for Rare Diseases to assess the knowledge of biosimilar for patients with cancer, immune-mediated inflammatory diseases, and rare diseases, more than 60% of the interviewees were not aware if a biologic could be used for their diseases. With reduced readiness to receive health information, which is one of the crucial elements of health literacy as defined by IAPO¹¹, one’s ability to take action for health enhancement would be limited as the patients were not empowered to make an informed decision. Structured communications with patients should be developed when starting them with a biosimilar to engage patients with informed decisions.

Conclusions

With the expiration of the patent of biologics, the market shares of biosimilars would definitely be growing. A lot more of originator biological products will soon lose their patency in the next 5–10 years. Therefore, we will expect that more biosimilar products will be on the market for our patients. Biosimilars may offer alternatives with lower costs for our patients. Nevertheless, healthcare professionals and patients have limited experiences with these biosimilar products. Continuous monitoring and research to ensure positive clinical, economic, and humanistic outcomes should be reinforced. The current article has commented on the regulatory issues in Hong Kong and overseas countries as well as the potential impact on both healthcare systems and patients upon the introduction of a biosimilar. It is important to have multidisciplinary team efforts including patients, healthcare professionals, academics, policy-makers, healthcare regulatory authorities, and government, to ensure medication safety of biosimilar products.

Transparency

Declaration of funding

This paper was not funded.

Declaration of financial/other interests

Both authors declare that they have no conflict of interests. One peer reviewer discloses that they are a shareholder in Matrix45, which has been contracted for work on biosimilars by Sandoz/Novartis, Teva, and Hospira/Pfizer. Per company policy, employees cannot contract individually with sponsor organizations and cannot hold equity in sponsor organizations. Another peer reviewer discloses that they have received research, speaking, and/or consulting support from a variety of companies, including Galderma, GSK/Stiefel, Almirall, Alvotech, Leo Pharma, BMS, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Ortho Dermatology, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate, and National Psoriasis Foundation. This reviewer also consults for Guidepoint Global, Gerson Lehrman, and other consulting organizations, and they are the founder and majority owner of www.DrScore.com, as well as the founder and part owner of Causa Research. The peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Acknowledgements

None reported.