Experience of reviewing the follow-on biologics including Somatropin and erythropoietin in Japan

To share the experience of reviewing clinical data required for the licensing of follow-on biologic products (biosimilar products and similar biotherapeutical products as EU and WHO terminology, respectively) in Japan, the data packages of two follow-on biologics, "Somatropin BS s.c. [Sandoz] (Omnitrope?)" and "Epoetin alfa BS [JCR]", which have been recently approved in Japan according to the "Guidelines for the Quality, Safety and Efficacy Assurance of Follow-on Biologics" published on March 4th 2009, are described. The clinical data package and indication of Somatropin BS/Omnitrope(?) were different in each country. In case of Epoetin alfa BS [JCR], non-clinical and clinical data-package was different from those of erythropoietin biosimilar products approved in EU. Submission of post-marketing surveillance plans for both products was required. Even though there seem to be differences in data requirements by each national regulatory authority, the accumulation of experience will provide the rationale and consensus on how to design the clinical trials for follow-on biologics.     

Clinical programs in the development of similar biotherapeutic products: rationale and general principles

Similar biotherapeutic products (SBPs) or biosimilars are biologics developed by pharmaceutical manufacturers to match originator biologics that have been on the market for a long time and lost their exclusivity (patent and market protection). The recently issued WHO guidelines on evaluation of SBPs provide clear guidance for manufacturers and regulators on how to develop and gain approval for these products. The present contribution illustrates the rationale for and general principles of the clinical programs used in the development of SBPs, taking the example of the three biosimilar products developed and marketed in Europe by Sandoz, namely growth hormone (Omnitrope?, the first ever EU biosimilar approval), erythropoietin α (Binocrit?), and filgrastim (Zarzio?).     

Worldwide experience with biosimilar development

Limited access for high-quality biologics due to cost of treatment constitutes an unmet medical need in the United States (US) and other regions of the world. The term “biosimilar” is used to designate a follow-on biologic that meets extremely high standards for comparability or similarity to the originator biologic drug that is approved for use in the same indications. Use of biosimilar products has already decreased the cost of treatment in many regions of the world, and now a regulatory pathway for approval of these products has been established in the US. The Food and Drug Administration (FDA) led the world with the regulatory concept of comparability, and the European Medicines Agency (EMA) was the first to apply this to biosimilars. Patents on the more complex biologics, especially monoclonal antibodies, are now beginning to expire and biosimilar versions of these important medicines are in development. The new Biologics Price Competition and Innovation Act allows the FDA to approve biosimilars, but it also allows the FDA to lead on the formal designation of interchangeability of biosimilars with their reference products. The FDA’s approval of biosimilars is critical to facilitating patient access to high-quality biologic medicines, and will allow society to afford the truly innovative molecules currently in the global biopharmaceutical industry’s pipeline.     

Health Canada/BIOTECanada Summit on regulatory and clinical topics related to subsequent entry biologics (biosimilars), Ottawa,Canada, 14 May 2012

In May 2012, Health Canada and other participants held a National Summit on Subsequent Entry Biologics (SEBs). Health Canada released a guidance document in March 2010 describing policy positions and data requirements for approval of SEBs. While Health Canada and health agencies in other regulatory jurisdictions are aligned on many scientific principles related to biosimilar drugs, Health Canada's specific requirements may not be widely understood by many Canadian stakeholders. The Summit provided an opportunity for education and dialog among physicians who prescribe biologics, provincial payers, and industry on the following topics: preclinical and clinical comparability studies; manufacturing and other product differences; extrapolation of indications; substitution and interchangeability of SEBs with reference biologic drugs in clinical practice; payers' current perspective; pharmacovigilance and naming. It is anticipated that the consensus reached at this meeting will further educate Canadian healthcare professionals, provincial payers, and insurers about the appropriate use of SEBs, and may be of general interest to others internationally.     

Bioanalytical strategy used in development of pharmacokinetic (PK) methods that support biosimilar programs

The development of biosimilar products is expected to grow rapidly over the next five years as a large number of approved biologics reach patent expiry. The pathway to regulatory approval requires that similarity of the biosimilar to the reference product be demonstrated through physiochemical and structural characterization, as well as within in vivo studies that compare the safety and efficacy profiles of the products. To support nonclinical and clinical studies pharmacokinetic (PK) assays are required to measure the biosimilar and reference products with comparable precision and accuracy. The most optimal approach is to develop a single PK assay, using a single analytical standard, for quantitative measurement of the biosimilar and reference products in serum matrix. Use of a single PK assay for quantification of multiple products requires a scientifically sound testing strategy to evaluate bioanalytical comparability of the test products within the method, and provide a solid data package to support the conclusions. To meet these objectives, a comprehensive approach with scientific rigor was applied to the development and characterization of PK assays that are used in support of biosimilar programs. Herein we describe the bioanalytical strategy and testing paradigm that has been used across several programs to determine bioanalytical comparability of the biosimilar and reference products. Data from one program is presented, with statistical results demonstrating the biosimilar and reference products were bioanalytically equivalent within the method. The cumulative work has established a framework for future biosimilar PK assay development.     

Bioanalytical strategy used in development of pharmacokinetic (PK) methods that support biosimilar programs

The development of biosimilar products is expected to grow rapidly over the next five years as a large number of approved biologics reach patent expiry. The pathway to regulatory approval requires that similarity of the biosimilar to the reference product be demonstrated through physiochemical and structural characterization, as well as within in vivo studies that compare the safety and efficacy profiles of the products. To support nonclinical and clinical studies pharmacokinetic (PK) assays are required to measure the biosimilar and reference products with comparable precision and accuracy. The most optimal approach is to develop a single PK assay, using a single analytical standard, for quantitative measurement of the biosimilar and reference products in serum matrix. Use of a single PK assay for quantification of multiple products requires a scientifically sound testing strategy to evaluate bioanalytical comparability of the test products within the method, and provide a solid data package to support the conclusions. To meet these objectives, a comprehensive approach with scientific rigor was applied to the development and characterization of PK assays that are used in support of biosimilar programs. Herein we describe the bioanalytical strategy and testing paradigm that has been used across several programs to determine bioanalytical comparability of the biosimilar and reference products. Data from one program is presented, with statistical results demonstrating the biosimilar and reference products were bioanalytically equivalent within the method. The cumulative work has established a framework for future biosimilar PK assay development.     

Worldwide experience with biosimilar development

Limited access for high-quality biologics due to cost of treatment constitutes an unmet medical need in the US and other regions of the world. The term “biosimilar” is used to designate a follow-on biologic that meets extremely high standards for comparability or similarity to the originator biologic drug that is approved for use in the same indications. Use of biosimilar products has already decreased the cost of treatment in many regions of the world and now a regulatory pathway for approval of these products has been established in the US. The Food and Drug Administration (FDA) led the world with the regulatory concept of comparability and the European Medicines Agency (EMA) was the first to apply this to biosimilars. Patents on the more complex biologics, especially monoclonal antibodies, are now beginning to expire and biosimilar versions of these important medicines are in development. The new Biologics Price Competition and Innovation Act (BPCIA) allows the FDA to approve biosimilars and allows the FDA to lead on the formal designation of interchangeability of biosimilars with their reference products. The FDA''s approval of biosimilars is critical to facilitating patient access to high-quality biologic medicines and will allow society to afford the truly innovative molecules currently in the global biopharmaceutical industry''s pipeline.Key words: monoclonal antibodies (mAbs), biosimilars, recombinant biopharmaceuticals     

Follow-on Biologics: A New Play for Big Pharma: Healthcare 2010

The U.S. pharmaceutical industry plays a vital role in shaping the face of American healthcare. As an industry rooted in innovation, its continued evolution is inherent. With major patent expirations looming and thin product pipelines, the industry now must consider new directions to maintain growth and stability. Follow-on biologics, derived from living organisms and marketed after the patent expiration of similar therapies, represent a growing opportunity for big pharmaceutical firms, as discussed during Yale’s Healthcare 2010 conference in April. Key characteristics of follow-on biologics make them a worthwhile investment for big pharma companies: They command high prices, will likely have fewer entrants than generics due to high barriers to entry, and play to the existing strengths of big pharma firms. With the recent healthcare legislation providing the way for consistent Food and Drug Administration (FDA) regulation, the timing seems right to continue the push into this new and growing market.At a time when healthcare issues are on the mind of every American, it would serve us well to consider the future of one of the most influential players in the sector: pharmaceutical companies. National health expenditures for pharmaceutical products are hovering around 10 percent, meaning that one out of every 10 dollars that we, as a nation, spend on healthcare goes toward drugs. These drugs regulate our cholesterol levels, promote the growth of white blood cells in cancer patients, manage our restless leg syndrome, help us sleep better at night, and provide myriad other benefits to our health and well-being. Yet, for all the benefits that the pharmaceutical industry provides, it is also criticized by many for the expense of its products and the high profit margins that these products command. The growing popularity of biologics — treatments derived from living organisms, such as antibodies and interleukins — has particularly increased the price of drugs in the United States. The current price of the average biologic is more than 20 times that of a traditional, chemically synthesized small-molecule drug. There is a trade-off between high prices and innovative new therapies. Moreover, pharmaceutical companies themselves argue justifiably that prices account not only for the price of production, but also for the research and development (R&D) for that therapy as well as numerous others that did not make it all the way through the regulatory process and to the clinic.In recent years, we have witnessed the breakdown of the well-oiled innovation machinery of the traditional big pharma company. While R&D departments spent more and more (well over $1B per drug), they did not see promising results in the form of late-stage drug candidates [1]. Over time, this led to a strategic shift in portfolio management within big pharma companies toward an acquisition-heavy plan to build up their pipeline of drugs. In-house R&D projects were cut, and layoffs of scientific staff were rampant. This phenomenon continues, with 2009 bearing witness to the most mergers and acquisitions in the pharmaceutical industry to date. Industry-wide consolidation aimed to find complementary development projects and synergies in manufacturing and emerging markets. What has been the effect of all of this? The answer is not as hopeful as the pharmaceutical industry would have liked. A giant “patent cliff” still persists, referring to a number of blockbuster drugs that will go off patent over the next two years and cause a dramatic decrease in sales for big pharma firms. Without a strong pipeline to fill in the valley with new product sales, big pharma companies have begun scrambling to find new ways to generate revenue.Meanwhile, the biotech industry’s foray into therapeutics has been a wild success story. From the 1980s to the present, biologics have reshaped the face of medicine in many disease areas. The spawn of highly innovative, nimble biotech firms, biologic drugs are large, complex molecules grown in living cells rather than synthesized chemically like small molecules. For example, Enbrel is a fusion protein that acts as a tumor necrosis factor (TNF) inhibitor to stop inflammation. This drug is being widely prescribed for rheumatoid arthritis as well as psoriasis, among other indications, with sales last year reaching $5.9 billion, up 9.3 percent from 2008 [2]. Enbrel was first developed by Immunex and released in 1998. Immunex was acquired by a rival biotech firm, Amgen, in 2001 [3], and subsequent marketing of the drug in the United States was jointly undertaken by Amgen and Wyeth (now taken over by Pfizer in the mega-merger of 2009). Enbrel’s is the classic story of the modern biologic: a novel therapy developed at a small biotech firm and acquired or licensed up the food chain to feed bigger firms’ appetites for late-stage assets.Enbrel is by no means unique; there are many blockbuster biologics on the market. Like Enbrel, many of them will reach the end of their patent life soon. Enbrel’s patent expiration is set for 2012, at which time it will be exposed to potential competition from generic versions. Therefore, though there are many novel biologics therapies that can provide new ways of treating patients, there is also a huge opportunity for generic versions of biologics that did not exist even one decade ago. This opportunity is hard to quantify, but one recent estimate shows that biologics responsible for $20B in annual sales will go off patent by 2015 [4]. Unsurprisingly, small-molecule generics firms are flocking to this space. Teva, the world’s largest generics manufacturer, has partnered with the Lonza Group to make and sell so-called follow-on biologics. These treatments are similar, but not identical, to preceding biologics whose patents expired. Meanwhile, Novartis’s generics arm, Sandoz, has increased capacity in biomanufacturing to ramp up its efforts. Big pharma itself has made motions of interest in the business of follow-on biologics, as witnessed by the dedicated division of Merck, BioVentures, established in late 2008 for the development of follow-on biologics. Interestingly, even Pfizer is testing a follow-on version of Enbrel, now in phase 2 clinical trials [5]. With a big market opportunity and a number of firms interested, follow-on biologics will surely play an important role in shaping the future of the pharma industry.For large pharmaceutical firms, what is needed is a way to diversify and mitigate risk, a way to supplement their rollercoaster sales figures year after year. Follow-on biologics may be a smart play for big pharma companies. Like their generic cousins, biologics manufacturing has strong economies of scale that big pharma firms can leverage. But unlike generics, there are higher barriers to entry because of the technical challenges of manufacturing biologics and the necessary clinical proofs of equivalency. Pharmaceutical companies already are practiced at navigating the global clinical-trials arena and should be able to exercise a significant competitive advantage in this area, especially over the existing generics manufacturers attempting a play in the follow-on biologics market. It has been estimated that the investment necessary to bring a follow-on biologic to market is eight to 10 years and will cost $100-$200M [6]. This investment of time and capital is substantial and tends to favor larger firms with significant R&D budgets. However, to put the investment into perspective, this is only one-tenth of the cost of developing a full-scale innovative pharmaceutical product and has less associated risk of failure — a proposition that the big pharma industry should find appealing. Additionally, the trend for current follow-on biologics on the market in the European Union (EU) and United States has been to use traditional detailing and marketing practices to compete with branded products. This, too, puts big pharma at a competitive advantage over other players lacking an army of detailing pharmaceutical reps, who can use their established relationships with doctors and medical personnel to promote new follow-on biologics.One counter-argument to the case for a move into follow-on biologics is that the new healthcare reform, the Patient Protection and Affordable Care Act (PPACA), passed in March of this year will harm any would-be generic biologics makers with its 12-year exclusivity for branded biologics. However, while this length of time is significantly longer than the proposed five years that generics proponents pushed for, the surety of a secure path forward through the FDA for follow-on biologics outweighs the downside of lengthy biologics exclusivity. It is reasonable to hope that within two to three years, the FDA will have functional guidelines for the regulation of this nascent market. Now more than at any other time in the past, the ambiguity associated with government regulation is manageable. And if big pharma becomes more intentional about entering the follow-on biologics market, its powerful lobby, PhRMA, could influence the way that the details of the FDA regulations are written.If the pharma industry does find the follow-on biologics market appealing and makes a bet on it for supplementary revenue, what can we expect from the patient perspective? It could mean greater access at cheaper prices, but the dynamics are much more nuanced. The economics of the small-molecule generics market likely will not be transferrable to the follow-on biologics market. High barriers to entry, high fixed costs of manufacturing, and marketing expenses will more likely manifest themselves in a market that has a small number of firms with relatively small price drops upon introduction of follow-on therapies. In small-molecule generics, the price typically decreases by about 80 percent from the original branded drug price after one year of generic competition. However, in current follow-on markets in the EU, this has not been the case. Since its introduction of biosimilars regulation in 2004, the EU has successfully introduced numerous follow-on biologics for three classes of branded drugs. The results hint at what might be expected for U.S. firms: By 2008 in Germany, biosimilars had captured an estimated 14 percent to 30 percent market share and discounted prices by 25 percent [7]. The U.S. story of follow-on biologics will likely mirror that of EU biosimilars rather than that of small-molecule generics.With healthcare legislation passed and the inevitable refocusing on bending the cost curve in healthcare expenditures, big pharma firms may be able to boost their reputation with the public as well as their bottom line with a continued push into follow-on biologics. The decreased risk of approval and steady returns will help diversify pharmaceutical companies’ volatile revenue streams, while concurrently winning favorable public opinion by promoting price reductions for some of the most expensive drugs available. The cost savings to consumers will increase access for patients as FDA regulation is finalized and more and more follow-on biologics enter the market. This could be a win-win scenario for big pharma and for patients.     

Evaluation of the structural,physicochemical, and biological characteristics of SB4, a biosimilar of etanercept

A biosimilar is a biological medicinal product that is comparable to a reference medicinal product in terms of quality, safety, and efficacy. SB4 was developed as a biosimilar to Enbrel® (etanercept) and was approved as Benepali®, the first biosimilar of etanercept licensed in the European Union (EU). The quality assessment of SB4 was performed in accordance with the ICH comparability guideline and the biosimilar guidelines of the European Medicines Agency and Food and Drug Administration. Extensive structural, physicochemical, and biological testing was performed with state-of-the-art technologies during a side-by-side comparison of the products. Similarity of critical quality attributes (CQAs) was evaluated on the basis of tolerance intervals established from quality data obtained from more than 60 lots of EU-sourced and US-sourced etanercept. Additional quality assessment was focused on a detailed investigation of immunogenicity-related quality attributes, including hydrophobic variants, high-molecular-weight (HMW) species, N-glycolylneuraminic acid (NGNA), and α-1,3-galactose. This comprehensive characterization study demonstrated that SB4 is highly similar to the reference product, Enbrel®, in structural, physicochemical, and biological quality attributes. In addition, the levels of potential immunogenicity-related quality attributes of SB4 such as hydrophobic variants, HMW aggregates, and α-1,3-galactose were less than those of the reference product.     

Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges

Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio?, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory.

We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.     

A decade of marketing approval of gene and cell-based therapies in the United States,European Union and Japan: An evaluation of regulatory decision-making

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.     

In-depth structural characterization of Kadcyla® (ado-trastuzumab emtansine) and its biosimilar candidate

The biopharmaceutical industry has become increasingly focused on developing biosimilars as less expensive therapeutic products. As a consequence, the regulatory approval of 2 antibody-drug conjugates (ADCs), Kadcyla® and Adcetris® has led to the development of biosimilar versions by companies located worldwide. Because of the increased complexity of ADC samples that results from the heterogeneity of conjugation, it is imperative that close attention be paid to the critical quality attributes (CQAs) that stem from the conjugation process during ADC biosimilar development process. A combination of physicochemical, immunological, and biological methods are warranted in order to demonstrate the identity, purity, concentration, and activity (potency or strength) of ADC samples. As described here, we performed extensive characterization of a lysine conjugated ADC, ado-trastuzumab emtansine, and compared its CQAs between the reference product (Kadcyla®) and a candidate biosimilar. Primary amino acid sequences, drug-to-antibody ratios (DARs), conjugation sites and site occupancy data were acquired and compared by LC/MS methods. Furthermore, thermal stability, free drug content, and impurities were analyzed to further determine the comparability of the 2 ADCs. Finally, biological activities were compared between Kadcyla® and biosimilar ADCs using a cytotoxic activity assay and a HER2 binding assay. The in-depth characterization helps to establish product CQAs, and is vital for ADC biosimilars development to ensure their comparability with the reference product, as well as product safety.     

Biosimilars in oncology and inflammatory diseases: current and future considerations for clinicians in Latin America

Biological therapies have revolutionized the treatment of several cancers and systemic immune-mediated inflammatory conditions. Expiry of patents protecting a number of biologics has provided the opportunity to commercialize highly similar versions, known as biosimilars. Biosimilars are approved by regulatory agencies via an independent pathway that requires extensive head-to-head comparison with the originator product. Biosimilars have the potential to provide savings to healthcare systems and expand patient access to biologics. In Latin American countries, regulatory frameworks for biosimilar approval have been introduced in recent years, and biosimilars of monoclonal antibody and fusion protein therapies are now emerging. However, the situation in this region is complicated by the presence of “non-comparable biotherapeutics” (also known as “intended copies”), which have not been rigorously compared with the originator product. We review the considerations for clinicians in Latin American countries, focusing on monoclonal antibody biosimilars relevant to oncology, rheumatology, gastroenterology, and dermatology.     

Biosimilars: Key regulatory considerations and similarity assessment tools

A biosimilar drug is defined in the US Food and Drug Administration (FDA) guidance document as a biopharmaceutical that is highly similar to an already licensed biologic product (referred to as the reference product) notwithstanding minor differences in clinically inactive components and for which there are no clinically meaningful differences in purity, potency, and safety between the two products. The development of biosimilars is a challenging, multistep process. Typically, the assessment of similarity involves comprehensive structural and functional characterization throughout the development of the biosimilar in an iterative manner and, if required by the local regulatory authority, an in vivo nonclinical evaluation, all conducted with direct comparison to the reference product. In addition, comparative clinical pharmacology studies are conducted with the reference product. The approval of biosimilars is highly regulated although varied across the globe in terms of nomenclature and the precise criteria for demonstrating similarity. Despite varied regulatory requirements, differences between the proposed biosimilar and the reference product must be supported by strong scientific evidence that these differences are not clinically meaningful. This review discusses the challenges faced by pharmaceutical companies in the development of biosimilars.     

The challenge of indication extrapolation for infliximab biosimilars

A biosimilar is intended to be highly similar to a reference biologic such that any differences in quality attributes (i.e., molecular characteristics) do not affect safety or efficacy. Achieving this benchmark for biologics, especially large glycoproteins such as monoclonal antibodies, is challenging given their complex structure and manufacturing. Regulatory guidance on biosimilars issued by the U.S. Food and Drug Administration, Health Canada and European Medicines Agency indicates that, in addition to a demonstration of a high degree of similarity in quality attributes, a reduced number of nonclinical and clinical comparative studies can be sufficient for approval. Following a tiered approach, clinical studies are required to address concerns about possible clinically significant differences that remain after laboratory and nonclinical evaluations. Consequently, a critical question arises: can clinical studies that satisfy concerns regarding safety and efficacy in one condition support “indication extrapolation” to other conditions? This question will be addressed by reviewing the case of a biosimilar to infliximab that was approved recently in South Korea, Europe, and Canada for multiple indications through extrapolation. The principles discussed should also apply to biosimilars of other monoclonal antibodies that are approved to treat multiple distinct conditions.     

Physicochemical and functional assessments demonstrating analytical similarity between rituximab biosimilar HLX01 and the MabThera®

Development of bio-therapeutics has exhibited exponential growth in China over the past decade. However, no biosimilar drug has been approved in China (CN) due to the lack of a national biosimilar regulatory guidance. HLX01, a rituximab biosimilar developed in China under European Medicines Agency biosimilar guidelines and requirements, was the first such drug submitted for regulatory review in China, and it is expected to receive approval there as a biosimilar product. To demonstrate the analytical similarities of HLX01, CN-rituximab (sourced in China but manufactured in Europe) and EU-rituximab (sourced and manufactured in Europe), an extensive 3-way physicochemical and functional similarity assessment using a series of orthogonal and state-of-the-art techniques was conducted, following the similarity requirement guidelines recently published by China’s Center for Drug Evaluation. The results of the similarity study showed an identical protein amino acid sequence and highly similar primary structures between HLX01 and the reference product (RP) MabThera®, along with high similarities in higher order structures, potency, integrity, purity and impurity profiles, biological and immunological binding functions, as well as degradation behaviors under stress conditions. In addition, HLX01 presented slightly lower aggregates and better photostability compared with the RP. Despite slight changes in relative abundance of glycan moieties and heavy chain C-terminal lysine modification, no differences in biological activities and immunological properties were observed between the RP and HLX01. In conclusion, HLX01 is highly similar to CN- and EU-sourced RP in terms of physicochemical properties and biological activities, suggesting similar product quality, ef?cacy, and safety. The regulatory requirements interpreted and applied towards the HLX01 marketing application sets a precedent for analytical similarity assessment of biosimilar products in China.     

Correct primary structure assessment and extensive glyco-profiling of cetuximab by a combination of intact,middle-up,middle-down and bottom-up ESI and MALDI mass spectrometry techniques

The European Medicines Agency received recently the first marketing authorization application for a biosimilar monoclonal antibody (mAb) and adopted the final guidelines on biosimilar mAbs and Fc-fusion proteins. The agency requires high similarity between biosimilar and reference products for approval. Specifically, the amino acid sequences must be identical. The glycosylation pattern of the antibody is also often considered to be a very important quality attribute due to its strong effect on quality, safety, immunogenicity, pharmacokinetics and potency. Here, we describe a case study of cetuximab, which has been marketed since 2004. Biosimilar versions of the product are now in the pipelines of numerous therapeutic antibody biosimilar developers. We applied a combination of intact, middle-down, middle-up and bottom-up electrospray ionization and matrix assisted laser desorption ionization mass spectrometry techniques to characterize the amino acid sequence and major post-translational modifications of the marketed cetuximab product, with special emphasis on glycosylation. Our results revealed a sequence error in the reported sequence of the light chain in databases and in publications, thus highlighting the potency of mass spectrometry to establish correct antibody sequences. We were also able to achieve a comprehensive identification of cetuximab’s glycoforms and glycosylation profile assessment on both Fab and Fc domains. Taken together, the reported approaches and data form a solid framework for the comparability of antibodies and their biosimilar candidates that could be further applied to routine structural assessments of these and other antibody-based products.     

The role of the quality assessment in the determination of overall biosimilarity: A simulated case study exercise

A determination of biosimilarity is based on a thorough characterization and comparison of the quality profiles of a similar biotherapeutic product and its reference biotherapeutic product. Although the general principles on the role of the quality assessment in a biosimilar evaluation are widely understood and agreed, detailed discussions have not been published yet. We try to bridge this gap by presenting a case study exercise based on fictional but realistic data to highlight key principles of an evaluation to determine the degree of similarity at the quality level. The case study comprises three examples for biosimilar monoclonal antibody candidates. The first describes a highly similar quality profile whereas the second and third show greater differences to the reference biotherapeutic product. The aim is to discuss whether the presented examples can be qualified as similar and which additional studies may be helpful in enabling a final assessment. The case study exercise was performed at the WHO implementation workshop for the WHO guidelines on quality assessment of similar biotherapeutic products held in Xiamen, China, in May 2012. The goal was to illustrate the interpretation of the comparative results at the quality level, the role of the quality assessment in the entire biosimilarity exercise and its influence on the clinical evaluation. This paper reflects the outcome of the exercise and discussion from Xiamen.     

Biosimilars: Challenges and path forward

Development of biosimilar proteins is the fastest growing sector in the biopharmaceutical industry, as patents for the top 10 best-selling biologics will expire within one decade. The world’s first biosimilar of infliximab, Remsima® (CT-P13) made by Celltrion, was approved by the Committee for Medicinal Products for Human Use (CHMP) of European Medicine Agency (EMA) in June 2013. This has ignited competition between related companies for prior occupation of the global market on blockbuster biologics. However, to achieve approval for biosimilars, developing companies face many hurdles in process development, manufacturing, analysis, clinical trials, and CMC (chemical, manufacturing and controls) documentation. Recent evolutionary progress in science, engineering, and process technology throughout the biopharmaceutical industry supports to show similarity between originator and biosimilar products. The totality of evidence has been able to demonstrate the quality, efficacy, and safety of biosimilars whereas a lack of interchangeability and international standards has to be addressed. Further understanding of the timing importance by regulatory agencies will be key to maximizing the value of biosimilars.