Biosimilar and it’s Current Perspective – A Review

 

Nikhil Kute*, S. D. Mankar, S. B. Bhawar

Pravara Rural College of Pharmacy, Pravaranagar.

 

ABSTRACT:

Biosimilars are biological products that are the replicas of their 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. 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. 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 in 2012.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:

“Biologics” represent one of the fastest growing segments of the pharmaceutical Industry. They refer broadly to substances produced by living cells using biotechnology (ie, recombinant DNA technology, controlled gene expression, or antibody Technologies), which have introduced many new treatments to life-threatening and rare Illnesses such as cancer, diabetes, anemia, rheumatoid arthritis and multiple sclerosis.

 

They involve a wide range of substances, including recombinant hormones, growth Factors, blood products, monoclonal antibody-based products, recombinant vaccines.

 

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

 

India approved its first biosimilar much before the United States and Europe. The first biosimilar was approved and marketed in India in 2000 for hepatitis B, although no specific guideline was available at that time for the development and marketing of biosimilar in India.

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 $580 million in 2012. In the Indian biotechnology market, Biopharmaceutical, which is the largest segment, accounted for ~62% in 2020 and ~58% in 2019. The Indian biologics market is expected to register a CAGR of 22% from 2019 to 2025 to reach US$ 12 billion by 2025^3,4

 

How are biosimilars different from chemical generics?

 

One of the main problems that biosimilar drugs face is that many doctors and patients still cannot differentiate them from generic drugs, as they tend to believe both are simple copies of the original or reference drug. In fact, according to a survey created by the consultancy company PwC, 67% of consumers were not sure what a biosimilar was, and 16% chose an incorrect response to the question about what a biosimilar was (PwC Health Research Institute, December 2015). Even though both biosimilars and generic drugs have the same commercial basis, meaning they are marketed when the patent of the original drug they come from has expired, they are two completely different products when it comes to their structure, development and authorisation. Below we will see the main differences between biosimilars and generic drugs.Generic drugs are simple molecules that are easy to characterise and have a small, well-defined structure (approximately 180daltons on average).⁵ However, biosimilars are very complex molecules with many post-translational modifications. They can exceed 150,000 daltons in size in the case of monoclonal antibodies and require a lot of analytical work for their structural and functional characterisation. Furthermore, generic drugs are very stable molecules, making them easy to store. However, just like many biological molecules, biosimilars are very sensitive to storage and handling conditions, so they need to be stored under adequate conditions starting from when they are developed. Another difference between the two products is that generic drugs have virtually no immunogenic potential, which means they cannot generate an immune response, while biosimilars, just like biological reference drugs, could be immunogenic. 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 safety⁶

Difference:

Process	Biosimilar	Generic
Manufacturing	Produced by biological process in host cell lines   Sensitive to production process Changes expensive and specialized production facilities.   Reproducibility difficult to establish	Produced by using chemical synthesis     Less sensitive to production process Changes       Reproducibility easy to establish
Clinical   development	Extensive clinical studies, including Phase I–III Pharmacovigilance and periodic safety updates needed	Often only Phase I studies   Short timeline for approval
Regulation	Needs to demonstrate “similarity” Regulatory pathway defined by Europe (EMEA)   No automatic substitution allowed	Needs to show bioequivalence   Abbreviated registration procedures in Europe and US   Automatic substitution allowed

Abbreviation:  Emea, European Medicine Agenc

 

Current Status:

Biological products approved in India:

History of biological products in India: Recombinant hepatitis-B-surface Antigen was the first indigenously developed and commercialized Biopharmaceuticals in the year 1997. Several biopharmaceuticals have been indigenously developed and have received approval the last 13 years.

 

India has a thriving biosimilar ecosystem in comparison to other countries and because of that Indian pharmaceutical companies have risen as the global market leaders in biosimilars. India approved its first biosimilar much before the United States and Europe Currently, there are 98 approved biosimilars in India, with at least 50 on the market, the most of any country in the world^.7

 

Regulatory approval process for biological products:

Biological products are considered as NEW DRUGS as per the Indian “Drugs and Cosmetics Act.” Products intended to be marketed in India Are regulated by either drug Controller General of India or by DCGI or by DCGI and Department of Biotechnology (DBT). The history regulatory related to drug import, manufacture and sale are covered under the Drugs and Cosmetics Act of 1940 and Drugs and Cosmetics Rules of 1945. The Act’s main objective is to ensure that available human drugs Are safe efficacious and conform to prescribed quality standards, and Marketed cosmetics are safe for use. CDSCO office along with the Indian Council of Medical Research have adopted international regulatory Guidelines for biomedical research on human subjects in 2000 and Indian GCP guidelines were released by CDSCO office and Guidance On Common Technical document for the NDA application were other Initiatives for streamlining the requirements for conducting clinical Trial and new drug approval process in India^.7 CURRENTLY, clinical trials in India are regulated by Schedule Y of the Drug and Cosmetics Rules, 1945. During the amendment of drugs and Cosmetics rules, 2005, the Schedule Y was extensively revised to bring The Indian regulations on par with internationally accepted definitions and procedures. Schedule Y defines the requirement and guidelines for and/or manufacture of new drugs for sale of clinical trials.⁸

 

Issues of concern with use of biosimilar:

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.⁹ 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.¹⁰ 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.¹¹

 

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. 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.¹² 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.¹³ In another study, many patients treated with recombinant interferons demonstrated the presence of neutralizing antibodies that significantly suppress their own production.¹³ 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. 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.¹⁴

 

Pharmacovigiliance: 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.¹⁵

 

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.¹⁶

 

 

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. 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.¹⁷

 

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. In February 2006, EMEA released guidelines containing details of clinical, nonclinical and quality expectations for biosimilars.¹⁸ Based on these guidelines, EMEA has approved biosimilars of somatropin (omnitrope, valtropin), epoietin (abseamed, binacrit, hexal, silapo, retacrit) and G-CSF (ratiograstim, biograstim, tevagrastim). EMEA has rejected marketing applications for aplheon, the biogeneric of interferon, due to the concerns over manufacturing technique and quality control. The application of biosimilar Marvel Insulin was also disapproved because of inadequate data to prove similarity with innovator product.¹⁸ French legislation and Spanish ministry of health and consumer affairs have also issued the law that prevents one biological medicine being substituted for another. US-FDA and several other regulatory agencies are still working on formulation of guidelines for marketing approval of biosimilarsIn India, the specific guidelines for approval of biosimilars are lacking. Thus, there is unrestrained flooding of biosimilars in Indian market.¹⁹

 

FDA Approach Regarding the Use of Biosimilar Drugs:

FDA was given the authority to approve biosimilars, including Interchangeable, to maintain safety, efficacy, and quality of Biosimilar product. Biologics Price Competition and Innovation Act of 2009 authorizes the FDA to oversee an “abbreviated pathway” for approval of biologics that are “biosimilar” to already approved products. The abbreviated Pathway will eliminate unnecessary and unethical testing Of biosimilars in animal and human. This will save the Time, money and manpower. The Patient Protection and Affordable Care Act of 2010 (USA) also supports this. Introduction of biosimilars also requires a specifically Designed pharmacovigilance plan.²⁰

 

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).^17,20 EMEA has rejected marketing applications for aplheon, the biogeneric of interferon, due to the concerns over manufacturing technique and quality control.^17,20 The application of biosimilar Marvel Insulin was also disapproved because of inadequate data to prove similarity with innovator product.²¹

 

French legislation and Spanish ministry of health and consumer affairs have also issued the law that prevents one biological medicine being substituted for another. US-FDA and several other regulatory agencies are still working on formulation of guidelines for marketing approval of biosimilars. In India, the specific guidelines for approval of biosimilars are lacking. Thus, there is unrestrained flooding of biosimilars in Indian market.²²

 

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. 

 

REFERENCES:

1.     Alten R, Cronstein BN (2015) Clinical trial development for biosimilars. Semin Arthritis Rheum 44(2015): S2–S8

2.     Nowicki M. Basic facts about Biosimilars. Kidney Blood Press Res. 2007; 30: 267–72.[PubMed] [Google Scholar]

3.     Arbogast LW, Delaglio F, Schiel JE, Marino JP (2017) Multivariate analysis of 2D 1H, 13C methyl NMR spectra of monoclonal antibody therapeutics to facilitate assessment of higher order structure. Anal Chem 89(21):11839–11845.

4.     Biosimilar medicines: Overview [Internet]. London (UK): European Medicines Agency; c1995–2018 [cited 2019 Jan 5]. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/general/general_content_001832.jsp&mid=WC0b01ac0580bb8fda. Accessed 5 Jan 2019

5.     Yang Danlin, Singh Ajit, Helen Wu, Kroe-Barret Rachel (2016) Comparison of biosensor platforms in the evaluation of high affinity antibody-antigen binding kinetics. Anal Biochem 508:78–96.

6.     DiMasi JA, Grabowski HG, Hansen RW (2016) Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ 47:20–33.

7.     Aladul, M.I.; Fitzpatrick, R.W.; Chapman, S.R. Healthcare professionals’ perceptions and perspectives on biosimilar medicines and the barriers and facilitators to their prescribing in UK: A qualitative study. BMJ Open 2018, 8, 11 e023603.

8.     Giuliani, R.; Tabernero, J.; Cardoso, F.; McGregor, K.H.; Vyas, M.; De Vries, E.G.E. Knowledge and use of biosimilars in oncology: A survey by the European Society for Medical Oncology. ESMO Open 2019, 4, e000460.

9.     Park, S.K.; Moon, W.; Kim, E.S.; Park, S.H.; Park, D. Il Knowledge and Viewpoints on Biosimilar Monoclonal Antibodies among Asian Physicians: Comparison with European Physicians. Korean J. Gastroenterol. 2019, 74, 333–340.

10.   Schellekens H. Biosimilarepoetins: How similar are they? Eur J Hosp Pharm. 2004;3:43–7.[Google Scholar]

11.   Haselbeck A. Epoetins: Differences and their relevance to immunogenicity. Curr Med Res Opin. 2003;19:430–2. [PubMed] [Google Scholar]

12.   Locatelli F, Del Vecchio L, Pozzoni P. Pure red-cell aplasia “epidemic”—mystery completely revealed? Perit Dial Int. 2007;27(Suppl 2):303–7.[PubMed] [Google Scholar]

13.   Oberg K, Alm G. The incidence and clinical significance of antibodies to interferon-α in patients with solid tumors. Biotherapy. 1997;10:1–5. [PubMed] [Google Scholar]

14.   Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241–8. [PubMed] [Google Scholar]

15.   Locatelli F, Roger S. Comparative testing and pharmacovigilance of biosimilars. Nephrol Dial Transplant. 2006;21(Suppl 5):13–6. [PubMed] [Google Scholar]

16.   Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol. 2008;19:411–9. [PubMed] [Google Scholar]

17.   Duerden M. Prescribing advice needed for new biosimilar biological drugs. Prescriber. 2007;18:1–2. [Google Scholar]

18.   Joshi SR. BiosimilarInsulins: Are they really ‘similar′? JAPI. 2009;57:38–41. [Google Scholar]

19.   Europa BIO. Bioindustry welcomes new French legislation covering biosimilar medicines. [Last accessedon 2007 Feb 21]. Available from:http://www.europabio.be/articles/PR_Biosimilars_070221_FINAL.pdf .

20.   Hodgson J. WHO guidelines presage US biosimilars legislation? Nat Biotechnol. 2009;27:963–5. [PubMed] [Google Scholar]

21.   Hodgson J. WHO guidelines presage US biosimilars legislation? Nat Biotechnol 2009;27:963‑5.

22.   C. Baldamus, S. Krivoshiev, M. Wolf-Pflugmann, et al. Long-term safety and tolerability of epoetin zeta, administered intravenously, for maintenance treatment of renal anemia Adv Ther, 25 (2008), pp. 1215-1228

 

 

Received on 11.01.2022       Modified on 27.01.2022

Accepted on 10.02.2022     ©A&V Publications All right reserved