The Differences Between Biosimilar And Generic Drugs

Published Date: 02 Nov 2017

1. Introduction

There has been a fastest growing of "biologic" in the pharmaceutical industry. Biologic or biopharmaceutical drugs have their substances that derived from a living organism. A various substances of biologics include recombinant hormones and vaccines, blood products, growth factors, monoclonal antibody-based products, gene and cell therapy biological products. These substances are produced by recombinant DNA, antibody technologies and controlled gene expression. This made it ability to introduce many new treatments for some rare illnesses such as rheumatoid arthritis, multiple sclerosis, anemia diabetes and cancer. The first biopharmaceutical drug Humulin was approval in 1982 by US Food and Drug Administration (FDA), since the global biologic industry has witnessed a development and change in order to enter pharmaceutical market.2. It has been seen that the generic versions of original innovator products are attempting to reduce its cost under an increase pressure on healthcare budgets(5-9). Today, generic versions of biologics are introduced in pharma market, these versions referred to different names as "subsequent entry biologics" in Canada, "biocomparables" in Mexico, "biosimilars" in Europe, "follow-on pharmaceuticals" in the US and Japan. These terms arise from loss of patent protection by many first generation innovator products in the last few years, and the expectation that a few more will suffer the same fate in the next few years.

The differences between biosimilar and generic drugs

Generic drugs are generally produced by chemical methods and are characterized due to their chemical and therapeutic equivalence to the branded, original, low molecular weight chemical drugs whose patents have expired. These are essentially identical to the original product and sold under a common name. The approval of generic drugs is a simplified registration procedure, with demonstration of bioequivalence.[5] by abbreviated new drug application (ANDA). However, these standards are not suitable for biosimilars because of various differences exist between generic drugs and biosimilars:

Compared with low molecular weight and structurally well defined chemical drugs, biopharmaceuticals are larger in molecular weight compounds with a complexity of three-dimensional structure. For instance molecular weight of interferon B is 19,000 Da, while molecular weight of aspirin is 180 Da. The typically biologic with several hundred amino acids, is 100 to 1000 times larger in size than chemical drugs. Due to the complexity in structure and high molecular weight, the characterization of biopharmaceutical becomes an challenge. In contrast, generic drugs are easy to reproduce and specify by appropriate tool such as mass spectroscopy [6,7].

In addition, the manufacturing processes of biotechnological medicines are more complex than generic drugs. The manufacturer of biosimilar is a proprietary knowledge and is not be similar to the manufacturing process of an innovator product. As a result, the copy is seemed to be impossible for any protein product. This because of the difference cell lines, purification and extraction techniques and protein sources are used in different manufacturing processes of biosimilars. This feature result in the heterogeneity of biologics. Another difference between biopharmaceuticals and chemical drugs is Immunogenicity. Biosimilar may decrease efficacy or have an adverse effect due to the neutralization of endogenous factors (26).

2. Approved biosimilars; biosimilars in clinical development.

There are 14 biosimilars approval in EU (table2), all of these are versions of epoetin (EPO), Somatropin and filgrastim.

Table 2: Approval biosimolar in EU

EMEA stated that in clinical development, comparative PK and PD studies of biosimilars should be used in healthy volunteers under the comparative efficacy and tolerability trials. PK/PD studies, in some cases could be seen as a sufficiency (15); in other cases, for instance the mechanism of action of the drug is only regulated by its interaction with biding partners as the target, therapeutic similarity demonstrated in one indication may be extrapolated to other indications of the reference product. There has been a debate tconcern about the different indications such as the use oj The different doses (19) and different patient populations, children versus adults, or when extrapolation to use in healthy individuals is concerned, for example, use of filgrastim for stem cell mobilization and collection in healthy donors . Also, the guidelines of EMEA put an attention on the assessment of the clinical tolerability of biosimilars due to its immunogenicity. During the control process, the differences in quality attributes between the biosimilar and its reference product are not always detected; and the clinical consequences of biosimilars and reference products are not always predicted by non-clinical animal studies [6]. Therefore, clinical trials are indispensable for evaluating the immunogenicity and tolerability of biosimilars These assessments include the characterization of the observed immune response, antibody testing and the evaluation of the correlation between antibodies and their effects on PKs, PDs, efficacy and tolerability. It is also seen that the risk of immunogenicity might differ within biosimilars, which depend on the therapeutic indication. Also, immunogenicity is a long-term event, gathering of immunogenicity data after marketing authorization remains an important prerequisite. Consequently, within the authorisation procedure, the company applying for regulatory approval of a biosimilar, as for any newly approved biopharmaceutical, should also provide plans for post-marketing surveillance including a risk management programme.

3. Challenges to the emergence of biosimilars.

4.1 Assessment of similarity of biosimilars with their originator biopharmaceutical product

One of the biggest challenges in manufacturing biosimilars is to demonstrate the sufficient similarity comparing with the original product, apart from ensuring consistent quality between different rounds of biosimilars produced in their own manufacturing facilities. In addition, the consistent efficacy of a new product needs to be demonstrated in order to avoid the "overdosing" and adverse effects. In guidelines of EMEA for pre-market and post matket authorization of biosimilars stated that an extensive testing are needed to ensure that biosimilars are similar as their reference product in quality, safety and efficacy (6). There are many in vitro tests, which are used in order to compare the structure of biosimilars and their originator molecules (19). However, these in vivo tests have a limitation in predicting the biological activities in vivo of biosimilars. The differences of biological activity may exist in both biosimilars and originator product even they have a similarity in size and structure. The biological activity can be influenced by the packaging, formulation of product , in addition to protein aggregates, impurities and cold chain handling (17). Also, biological activity is hard to assess sufficiently due to the trial results in animal models can not be extrapolated to humans. Thus, to demonstrate the similarity between biosimilars and originator product, the controlled clinical trials are seemed to be the most reliable means (25) and Post-marketing surveillance may be another evidence for the safety and efficacy of biosimilars (16). . .

4.2 Analytical techniques and their limitation in biosimilar approval parthway.

There are various analytical techniques to demonstrate the similarity and comparability a biosimilars product to a reference drug. These techniques refer to analyze the protein content , stability, impurities and additives, physiochemical integrity and immunogenicity. Size exclusion chromatography and ELISAs are used to analyze quantity, molecular weight of biosimilar . These techniques have a limitation because they require high-quality reference materials. In vivo and in vitro assay are used to measure biological properties. The purity of a product is measured by SDS-PAGE and RP-HPLC. These methods, however, may be limited by the availability of sufficiently large samples for processing and sample preparation is particularly labour intensive but are useful for detecting differences in physicochemical integrity and glycosylation patterns between similar products [9,10. Additives (e.g. human serum albumin (HSA), polysorbates, glycine, amino acids, calcium chloride and urea) are also used to stabilize protein drugs [11]. However, the additives may also influence a drug’s safety profile. The radio immune precipitation assay (RIPA) is a sensitive assay for detecting high affinity antibodies [17]. However, the use of radioactive material and labour-intensive protocols makes it inappropriate. Pharmacovigilance, as part of a comprehensive risk management programme, will need to include regular testing for consistent manufacturing of the drug.

4.3 The requirement of the state of the art

It is considered that by using the state of the art analytical methods have enhanced the demonstration of similarity of biosimilars, comparing with reference product. This technique is able to to detect a slight difference between biosimilars and reference product for quality evaluation. The comparability exercises of the state of the art technique include the comparative evaluation of biological activity by using bioassays, physicochemical parameters and the comparative assessment of impurity and purity profiles. It is seen that the differences with biological products are dur to the different type of cell culture, the storage conditions, the growth conditions, the formulation and the purification process. The CHMP also requires that the quality attributes of biosimilars and reference product are need to be compared and justified to find any differences in relation to the efficacy and tolerability ; such as differences in impurity profiles or variability in post-translational modifications. . For example, for a biosimilar of epoetin alfa, differences are reported with respect to glycosylation (higher levels of phosphorylated high-mannose-type structures, lower levels of N-glycolylneuraminic acid and diacetylated neuramic acids) and oxidation (lower levels of the oxidised variant). For a biosimilar of somatropin, differences in impurities are reported as well as a higher level of deamidated variants.

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4. Regulatory issues and considerations, comparison of the regulatory landscapes associated with approval of biosimilars in various countries

The regulation for approval of biosimilars is different and more complex than the generic innovator product due to some reasons, such as a valid study to demonstrate the similarity of biosimilars and the limitation of analytical test. Modest differences might result in different clinical implications and a adverse effects on patients. Thus, valid preclinical and clinical studies for assessing the clinical efficacy and safety are considered to be important for marketing biosimilars (19,29,31). From this point, EMEA has issued a number of general guidelines, which are required for biosimilar approval in pharma market. (Table 3-32-41). Product-class-specific guidelines include human insulin, human granulocyte colony-stimulating factor, somatotropin, erythropoietin, recombinant IFN-a, and herarins (table 3). Different products have a different approval process and based on case by case basis assessment. (42).

In US the FDA stated that there is no other biosimilar approval when a specific regulation has been issued, since the approval of Ommitrope in 2006(43). The Pathway for Biosimilars Act of 2009 and the Patient Protection and Affordable Care Act of 2010 have gave a greater clarity and clear mandate for FDA for the assessment of biological product approval. In Canada, Omnitropeâ„¢ was the first Subsequent Entry Biologic (SEB) approval in 2009 . Recently, a finalized guidance document as an administrative aid to guide SEB decision-making has been provided for approval of SEBs (44).

In other countries such as Australia, , Japan, Turkey, India, China the regulatory framework for approval of biosimilars is still evolving. Thus it is considered that a global agreement on guidelines and criteria for biosimilars is needed. This will have an positive impact on economic aspect, scientific principles and patients.

5. Impact on the global industry; future prospects; references.

In 2011 the total biologics market was estimated $157 bn and in 2016 it is forcast of $200-210 bn biologic market. (1). Currently, approximately 270 monoclonal antibodies are studying in phase II and III. This is expected that almost 80 tonnes of monoclonal antibodies with more than 10% of biosimilar monoclonal antibodies might be produced in 2020 with the improvement of quality and cell culture production. A 4.3% compound annual growth rate (CAGR) of biologic sales is estimated during 2010-2016, with $89.9 bn worth of biologic due to the expiration in 2016. This provides an opportunity for the increase in biosimolar manufactures. Global biosimilar sales have increased from 14 m in 2006 to 693 m in 2011 since the first biosimilar somatropin was introduced in Europe in 2006; and it is predicted to be increase to 4-6 m in 2016 and occupy for 2% of total biologic market(1-3). The modest growth is due to the remain of patent protection, lack of flexibility and market exclusivity around the interchangeability.

In conclusion biosimilars are complex molecules, many factors such as the structural similarity, manufacturing process, quality of pharmacodynamic assays, the understanding of the mechanism of action, the concept of comparability of immunogenicity and pharmacokinetic, the innovator’s experience and quantity and quality of clinical data are considered to be important for biosimilars approval. It is also noted that the safety and efficacy of biosimilar are vital for patient safety. Thus, the non clinical and clinical trials are both required to determine these aspects. Futher the global regulatory framework for biosimilar approvals is a need for it development and deal with its challenges. Although biosimilars have begun to enter the global market, the biosimilar manufacturers’ long-term capability to manufacture a consistent product still remains to be proven. At present, even though European legislation is in place to assess and grant marketing approval for biosimilars, the EMEA guidelines only provide a road map and leave challenging areas still to be explored and monitored. Approvals of biosimilar products should continue to be dealt with on a case-by-case basis.