BIOSIMILARS AND ITS REGULATORY CONSIDERATIONS

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About Author:
Mahendra N. Suthar
M.S.Pharm. Biotechnology,
National Institute of Pharmaceutical Education and Research,
Mohali, Punjab-160062.
mahendramevada8@gmail.com

Abstracts:
Biosimilars are protein product that are similar to branded biologics and approved by regulatory agencies.  Biosimilars are cost effective and relatively cheaper than branded biologics. In pharmaceutical industry Biosimilars segments became one of the larger and lucrative one. The global Biosimilar segment has attended higher growth rate among them the USA and Europe are leading one. Further it very good opportunity for Pharmergings like India, China, Russia, Brazil etc. Specially India can replicate its well developed genetic segments and can attend higher growth in it. But, certain issues including immunogenicity, marketing competition and regulatory hurdles are needed to be addressed to propel further innovation in this segment. In present review various marketing opportunities, key issues and regulatory consideration for Biosimilars is described in detail.


REFERENCE ID: PHARMATUTOR-ART-1851

1. Introduction
Biosimilars are follow-on version of biologics; they are also known as biogenetics and launched after patent expiry of branded biologics1, 2, 3. After development of Omnitope (Human Growth hormone) by Sendoz in 2006 and get approved by European Medicines Agency (EMEA), saga of Biosimilars was started3, 4. Now a day Biosimilars segments became one of the larger and lucrative among the pharmaceutical industry of the globe. Biosimilars are seen cost effective alternative to high priced branded biologics2, 3. But still it faces many issues like, immunogenicity, efficacy, high development cost, regulatory hurdles and stiff marketing competition3,5. Various opportunities, issues and regulatory consideration of Biosimilars are discussed in coming section of this review.

2. Introduction of Biosimilars
Biosimilars are follow-on version of biologics; they are independently developed after when patent has expired of already existing biological medicine, 2, 3,. More precisely it is defined as,

“Biological medical products whichis similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product and submitted to regulatory authorization by independent application after patent protection has expired for reference, 3, 6.


They are also known as follow on protein products6(USA).  Biosimilars are now firmly established by the European United (EU)   as copy biologics with a clear and effective regulatory route for approval, which allows marketing of safe and efficacious biological products4. It is also known as similar biological products5. Some time inconsistency in nomenclature is used like follow-on biologic, subsequent entry biologic, similar biotherapeutic product, similar biological medicinal product, biogeneric, me-too biologic, non-innovator biologic, bio-betters etc2, 3. But now a day several countries have adopted an identical or similar regulatory approach to the EU for approval of Biosimilars and furthermore, World Health Organization (WHO) has also adopted this terminology in order to achieve harmony in regulations of Biosimilars3, 7. So, “Biosimilars (EU)” and “follow on protein products (USA)’’ are most accepted name by regulatory authorities4, 6, 7.

Omnitrope (Growth hormone, used in treatment of growth disturbance) is the first Biosimilar approved by European medicines agency (EMEA) in 20064.  It is manufactured by the Swiss drug maker Novartis AG's generics unit Sandoz GmbH and it is independently developed from reference medicinal product Genotropin, which is manufactured by Pfizer3, 7. In 2011 FDA had approved M-Enoxaparin of Momenta Pharmaceuticals; Biosimilar version of sanofi-aventis’s blockbuster blood thinning drug, Lovenox (enoxaparin sodium)3, 5. Recently (Aprile-2013) Cipla has launched the first Biosimilar’ ‘’ETACEPT’’; from reference molecule Etarnercept in Indian market and it became a first Biosimilars for India8.

3. Biosimilars market at a glance
In 2011 global market of Biosimilars was around $2.5 billion and in 2012 it reached up to $3 billion9, 10. In present scenario it grows by about 20% compound annual growth rate (CAGR) at will reach around $7 billion in 201510, 11. In competitive front, Sandoz is leader in global market; Teva and Hospira are also major player in Biosimilars market9, 10. Low molecular weight heparin (LMWH), Growth hormones, Interleukines, Insulin etc. has high demand in pharmaceutical industry10.

Figure 1: Global Demands of various biologics

Before 2020 around $67 billion biological will go off-patented and they will come in segment of Biosimilars which will add bloom to business of Biosimilars12. Patent cliff of branded biologics is important factor for growth of Biosimilar segments1, 12. The patent protection of Epogen (Epoetin alfa) and Neulasta (Pegfilgrastrin) has already expired and following block blusters biologics will go off patented in the coming decade.

Table 1: Patent expiry date of branded biologics in EU and USA4, 6, 12, 13


India is one of the biggest sources of generic industry and is one of emerging market with high population14, 15. So, by replicating generics trends India becoming emerging and bigger hub for Biosimilars production and marketing14, 15. In India Dr. Reddy’s lab, Shantha Biotech, Intas, Cipla, Biocon, Reliance Life Science, Wockhardt etc. are major player of Biosimilars production14, 15. In 2008 around $200 million sales was recordedand in 2012 was reached around $580 million14, 15. It saw that Indian Biosimilars market grows by 30% CAGR. In coming time India will dominate in the globe like generic drug market14, 15.

4. Key issues with Biosimilars

1. Higher development cost but bridge to bloom
Development of Biosimilars is costlier compared to development of traditional generic drug. Development of Biosimilars requires higher R&D, manufacturing and approval cost, longer development time and further it has a sort half life16. Various industrial reports indicate that around 2 to 5 years and around $10 to $100 million investment required for development of Biosimilars16. Further it is no guaranty of success. But ones it get approval it gives higher rewards16.

Biosimilars are priced only 20% to 30% lesser price to reference branded drugs16and further Biosimilars are seen cost effective alternative to high priced branded biologics, offering cost advantages to both player and patients17, 18. Due to complex structure it is not easy to copy it. Some of branded biologics company file application for their off patented drugs and enjoy further monopoly in the market17.

2. Safely and efficiency issue
Due to larger biological structure and heterogeneity immunogenicity and patient safety is a prime concern for Biosimilars, further it is difficult to predict and can be medical emergency18, 19. For example in EU-licensed version of erythropoietin caused severe immunogenicity reactions while no USA cases were observed20. The recent EMEA guidelines on comparability of Biosimilars state that preclinical data may be insufficient to demonstrate immunologic safety of some Biosimilars4, 19.In these cases, the immunological safety can only be demonstrated in cohorts of patients enrolled in clinical trials and post marketing surveillance19.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 assays19.

In vitro bioavailability saw significant difference; some time it saws 20% to 120% variation. Thus, it is not easy to determine bioavailability of Biosimilars by in vitro bioequivalence study21. Only clinical data obtained from cohort of patients is suitable to compare it with reference biologic.  Some time it saw significant difference in patient to patient, so more research is required to establish suitable bioequivalence models21.

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