Biosimilars: current perspectives and future implications.

Biosimilars are biological products that are the replicas of their innovator biopharmaceuticals. These are developed after patent expiration of innovator biopharmaceuticals and are submitted for separate marketing approval. In view of the structural and manufacturing complexities of biopharmaceuticals, biosimilars should not be considered as "biological generics". These are rather unique molecules with limited data at time of approval, so there are concerns about the safety and efficacy of biosimilars. This article will address the differences between biosimilars and chemical generics, issues of concern with the use of biosimilars and need of appropriate regulations for their approval.

Introduction

Biopharmaceutical drugs have become an essential part of modern pharmacotherapy. These comprise proteins derived from recombinant DNA technology and hybridoma technique. Examples include biological proteins (cytokines, hormones, and clotting factors), monoclonal antibodies, vaccines, cell and tissue based therapies. Living organisms such as plant and animal cells, bacteria, viruses and yeast are employed for the production of biopharmaceuticals.

Biopharmaceuticals have potential to reach up to 50% share in global pharmaceutical market in the next few years.[1] The expiry of patent protection of many biopharmaceuticals has initiated the development of a category of alternative versions of innovator biopharmaceuticals known as biosimilars. Because of the structural and manufacturing complexities, these biological products are considered as similar, but not generic equivalents of innovator biopharmaceuticals. The term “biosimilar” is in common use in the European Union, while the term “follow on biologics” is more popular in the American context.[1]

At present, India is one of the leading contributors in the world biosimilar market. India has demonstrated the greatest acceptance of biosimilars, which is reflected from over 50 biopharmaceutical brands getting marketing approval.[2] The Indian biotechnology industry is also gaining momentum, with revenues of over U.S. $ 2.0 billion in 2006, 70% of which is biopharmaceuticals. These are projected to reach up to $580 million by 2012.[34]

Owing to affordability and easy accessibility, biosimilars have established a good reputation among healthcare professionals. Though biosimilars are gaining popularity in national and international markets, it is important to remember that the biosimilars are not biological generics. These are rather unique molecules which are supported by only limited clinical data at the time of approval.[1] Therefore, there are concerns regarding their efficacy, long-term safety and immunogenicity.

How are biosimilars different from chemical generics?

Generic drugs are characterized by 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. These are approved through simplified registration procedure as abbreviated new drug application (ANDA), with demonstration of bioequivalence.[5] However, it is not possible to employ the same standards for the evaluation or appraisal of biosimilars, as there are various differences between chemical generics and biosimilars. Unlike structurally well-defined, low molecular weight chemical drugs, biopharmaceuticals are high molecular weight compounds with complex three-dimensional structure. For example, the molecular weight of aspirin is 180 Da whereas interferon-β is 19,000 Da. The typical biologic drug is 100 to 1000 times larger than small molecule chemical drugs and possesses fragile three-dimensional structure as compared to well-characterized one-dimensional structure of chemical drug. While chemical drugs are easy to reproduce and specify by mass spectroscopy and other techniques, there is a lack of appropriate investigative tools to define the composite structure of large proteins.[67] Moreover, the manufacturing processes leading to the production of biotechnological medicines are more complex. The manufacturers of biosimilar products will not have access to manufacturing process of innovator products, as this is a proprietary knowledge. Thus, it will be impossible to accurately duplicate any protein product. Different manufacturing processes use different cell lines, protein sources, and extraction and purification techniques, which result in heterogeneity of biopharmaceuticals. Versatile cell lines used to produce the proteins may have an impact on the gross structure of the protein, and may affect glycosylation and other post-translational modifications. Such alterations may significantly impact receptor binding, stability, pharmacokinetics and safety [Figure 1].[67] Immunogenic potential of therapeutic proteins is another unique safety issue which is not observed with chemical generics.[67]

Figure 1

Manufacture of biopharmaceuticals and sources of variation between manufacture of innovator biopharmaceutical and biosimilar

Issues of concern with use of biosimilars

Efficacy issues

Studies done in the past have demonstrated the differences between the bioactivity of the biosimilars and their innovator products. In a study comparing 11 epoetin alfa products from four different countries (Korea, Argentina, China, India), the isoform distribution among these products was variable and there were significant diversions from specification for in vivo bioactivity. For example, in vivo bioactivity ranged from 71 to 226%, with 5 products failing to fulfill their own specification.[8] With adequate hemoglobin monitoring, this variance in potency may not be a critical issue in interchanging epoetins. However, in case of monoclonal antibody therapy or treating a transplant rejection or a cancer patient, such variability would not be acceptable. A similar study compared quality parameters (such as identity, purity, content and efficacy) of several biosimilar brands taken from the Indian market and with those of the innovator drug products.[2] The study was carried out on 16 commercial brands covering three different biopharmaceuticals, which are, recombinant human pegylated G-CSF (granulocyte colony stimulating factor), recombinant human G-CSF and recombinant human erythropoietin. A marked lack of comparability between biosimilars and innovator products was seen. Also, a significant difference in the level of purity was observed among various brands of biosimilars of G-CSF and erythropoietin.[2]

Safety issues

The concern regarding immunogenicity is highlighted by the increase in number of cases of pure red cell aplasia associated with a specific formulation of epoetin alfa.[910] This episode made the world to look at biosimilars with caution. The immunological form of pure red cell aplasia was caused by the production of neutralizing antibodies against endogenous epoetin. Most of the cases occurred in patients treated with Eprex, the biosimilar of epoetin alfa, produced outside of the United States. The most likely cause was subtle changes in the manufacturing process. In the formulation Eprex, the human albumin stabilizer was replaced by polysorbate 80 and glycine. Polysorbate 80 is supposed to have increased the immunogenicity of Eprex by eliciting the formation of epoetin-containing micelles or by interacting with leachates released by the uncoated rubber stoppers of prefilled syringes.[910] In another study, many patients treated with recombinant interferons demonstrated the presence of neutralizing antibodies that significantly suppress their own production.[11] The development of pegylated thrombopoietin(megakarocyte growth and development factor) was stopped in clinical trials because of treatment-associated-thrombocytopenia in 13 of 325 healthy volunteers.[12]

The recent EMEA (European Medicines Agency) guidelines on comparability of biosimilars state that preclinical data may be insufficient to demonstrate immunologic safety of some biosimilars. In these cases, the immunological safety can only be demonstrated in cohorts of patients enrolled in clinical trials and post marketing surveillance. The radio immune precipitation assay and double antigen bridging ELISA assay are also sensitive assays for detecting high affinity antibodies. However, there is a need to validate and standardize these assays.[713]

Pharmacovigilance

Due to limited clinical database at the time of approval of a biosimilar, vigorous pharmacovigilance is required. Immunogenicity is a unique safety issue with biosimilars. However, lack of validation and standardization of methods for detection of immunogenicity further implies the necessity for robust pharmacovigilance. The adverse drugs reactions monitoring data should be exhaustive, including the type of adverse event and data about drug such as proprietary name, international nonproprietary name (INN) and dosage given.[17]

Substitution

Substitution allows the dispensing of generic drugs in place of prescribed innovator products. The rationale behind substitution of chemical drugs is that the original drugs and their generics are identical and have the same therapeutic effect. For majority of chemical generics, automatic substitution is appropriate and can produce cost savings. However, the same substitution rules should not be applied to biosimilars, as it may decrease the safety of therapy or cause therapeutic failure. The uncontrolled substitution of biosimilars also confounds accurate pharmacovigilance. If an adverse event emerges after switching from innovator biopharmaceutical to its biosimilar without documentation of product change, the event will not be able to be associated to a specific product or it will be ascribed to a wrong product during pharmacovigilance assessment. The prescribers and pharmacists should be aware of it and avoid this inappropriate substitution.[1714]

Naming and labeling

INN is the technical name for the medicinal products. The generic adaptation of chemical medicines is assigned the same name, as they are identical copies of the reference products. However, the biosimilars require unique INNs, as this would facilitate prescribing and dispensing of biopharmaceuticals and also aid in precise pharmacovigilance.[17] There should be comprehensive labeling of biosimilars including the deviations from innovator product and unique safety and efficacy data, which would assist the physician and pharmacist in making informed decisions.[1715]

Regulatory approval

Unlike chemical generics, the biosimilars require more stringent criteria for the evaluation of quality, safety and efficacy. In May 2004, the European parliament issued recommendations for regulatory approval of biosimilars. In February 2006, EMEA released guidelines containing details of clinical, nonclinical and quality expectations for biosimilars.[16] Based on these guidelines, EMEA has approved biosimilars of somatropin (omnitrope, valtropin), epoietin (abseamed, binacrit, hexal, silapo, retacrit) and G-CSF(ratiograstim, biograstim, tevagrastim).[1718] EMEA has rejected marketing applications for aplheon, the biogeneric of interferon, due to the concerns over manufacturing technique and quality control.[1718] The application of biosimilar Marvel Insulin was also disapproved because of inadequate data to prove similarity with innovator product.[1718]

French legislation and Spanish ministry of health and consumer affairs have also issued the law that prevents one biological medicine being substituted for another.[1920] US-FDA and several other regulatory agencies are still working on formulation of guidelines for marketing approval of biosimilars.[21] In India, the specific guidelines for approval of biosimilars are lacking.[418] Thus, there is unrestrained flooding of biosimilars in Indian market.

Conclusion

Biotechnological medicines shall become an important part of future healthcare landscape. With patent expiration of innovator products, the biosimilars will increasingly become available. Awareness of the deviations between biosimilars and innovator products in terms of efficacy, safety and immunogenicity is essential for proper prescription and safety of the patients.