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Page 1: Bio similars-scope & future prospects in india

“Bio-similars: Scope & future prospects

in India”Under the guidance of: By : Dr. J Venkata Rao Shradha BasuProfessor & HOD M.Pharm 1st yearDepartment of Biotechnology R. No. 130610001MCOPS MCOPS

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Contents Introduction Definitions Classifications Market overview Regulatory issues Regulatory guidelines Development process in India Approval process Forces shaping the biosimilar market Factors supporting biosimilar market Biosimilar market in India Specific company advancements Conclusions

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Introduction “The market for biologics is growing at twice the rate of

pharmaceutical drugs, placing significant cost pressures on government, employers, insurers, and patients.”

“Establishing a regulatory pathway for ‘follow-on’ biologics (bio-similars) was therefore felt to be necessary by many stake holders to encourage competition and reduce prices.”

“Many pharmaceutical companies – both large and small - are expecting their bottom line growth to be driven by bio-similars and are channelling their R&D budgets to compete in what – according to many - is going to be one of the hottest areas in a radically changing global pharmaceutical market.”

-QPS, global CRO

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DefinitionsAccording to the WHO, a bio-similar is a bio-

therapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference bio-therapeutic product.

According to the FDA, a bio-similar is a biological product that is highly similar to a US-licensed reference biological product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

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• According to the EMA, bio-similar is a medicinal product which is similar to a biological medicinal product that has already been authorised (the ‘biological reference medicinal product’). The active substance of a bio-similar medicinal product is similar to the one of the biological reference medicinal product. The name, appearance and packaging of a bio-similar medicinal product may differ to those of the biological reference medicinal product. It may also contain different inactive ingredients.

• India's definition : a biological product or drug produced by genetic engineering techniques and claimed to be "similar" in terms of quality, safety, efficacy to a reference innovator product, which has been granted a marketing authorization in India by a competent authority on the basis of a complete dossier, and with a history of safe use in India.

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• Biologics” represent one of the fastest growing segments of the pharmaceutical industry.

• They refer broadly to substances produced by living cells using biotechnology (i.e., 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, anaemia, 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, and advanced technology products (gene and cell therapy biological products).

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Bio-similars

Cytokines Interferons: INF-β, INF-ϒ, INF-α

etc.

Interleukins : IL-2, IL-3, IL-4, IL-6 etc.

TNF : TNF α

Nucleic acid therapeutics : plasmid DNA

Blood products & therapeutic enzymes :

Heparin, DNase etc.

Hormones of therapeutic

interest : Insulin, Glucagon, hGH

etc.

Growth factors : IGFs, EGFs, PDGF

etc.

Haemopoietic growth factors : G-CSF, M-CSF,

EPO etc.

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Market overview

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Regulatory issues

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Regulatory guidelines• FDA ( for USA)The Patient Protection and Affordable

Care ActI. Signed into law by President Obama on March 23,

2010II. Amends the Public Health Service Act (PHS Act)III. Create an abbreviated licensure pathway for

biological products that are demonstrated to be “bio-similar” to or “interchangeable” with an FDA-licensed biological product (pathway is provided as part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act).

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• EMEA (for Europe, Middle East, Africa )A total of 3 guidelinesFirst guidelineI. information on similar biological medicinal productsII. describes the concept of bio-similarsIII. the general principles to be applied in demonstrating

bio-similarityIV. Revised in May 2013Second guidelineI. the quality issues related to bio-similar developmentII. Revised in May 2012Third guideline I. addressing the clinical and non-clinical issues related

to bio-similars containing biotechnology-derived proteins as the active substance

II. addresses non-clinical and clinical requirements for marketing authorisation of a bio-similar

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EMA approved bio-similarsProduct name

Active substance

Therapeutic area

Authorization date

Manufacturer/Company name

Abseamed epoetin alfa AnaemiaCancerChronic kidney failure

28 Aug 2007 Medice Arzneimittel Pütter

Bemfola follitropin alfa Anovulation (IVF) CHMP positive opinion 23 Jan 2014

Finox Biotech

Binocrit epoetin alfa AnaemiaChronic kidney failure

28 Aug 2007 Sandoz

Biograstim filgrastim CancerHaematopoietic stem cell transplantationNeutropenia

15 Sep 2008 CT Arzneimittel

Epoetin alfa Hexal epoetin alfa AnaemiaCancerChronic kidney failure

28 Aug 2007 Hexal

Filgrastim Hexal filgrastim CancerHaematopoietic stem cell transplantationNeutropenia

6 Feb 2009 Hexal

Grastofil filgrastim Neutropenia 18 Oct 2013 Apotex

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Product name

Active substance

Therapeutic area

Authorization date

Manufacturer

Nivestim filgrastim CancerHaematopoietic stem cell transplantationNeutropenia

8 Jun 2010 Hospira

Omnitrope somatropin Pituitary dwarfismPrader-Willi syndromeTurner syndrome

12 Apr 2006 Sandoz

Ovaleap follitropin alfa Anovulation (IVF) 27 Sep 2013 Teva Pharma

Ratiograstim filgrastim CancerHaematopoietic stem cell transplantationNeutropenia

15 Sep 2008 Ratiopharm

Remsima infliximab Ankylosing spondylitisCrohn’s diseasePsoriatic arthritisPsoriasisRheumatoid arthritisUlcerative colitis

10 Sep 2013 Celltrion

Retacrit epoetin zeta AnaemiaAutologous blood transfusionCancerChronic kidney failure

18 Dec 2007 Hospira

Inflectra infliximab Ankylosing spondylitisCrohn’s diseasePsoriatic arthritisPsoriasisRheumatoid arthritisUlcerative colitis

10 Sep 2013 Hospira

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CDSCO, GEAC, RCGM (for India) Drugs and Cosmetics Act,1940; Drugs and Cosmetics

Rules,1945 & Rules for the manufacture, use, import, export and storage of hazardous microorganisms/genetically engineered organisms or cells,1989

Guidelines are as follows:I. Recombinant DNA Safety Guidelines, 1990II. Guidelines and Handbook for Institutional Biosafety

Committees (IBSCs), 2011III. Guidelines for generating preclinical and clinical data for

rDNA vaccines, diagnostics and other biologicals, 1999IV. CDSCO guidance for industry, 2008:-a) Submission of Clinical Trial Application for Evaluating Safety

and Efficacyb) Requirements for permission of New Drugs Approvalc) Post approval changes in biological products: Quality,

Safety and Efficacy Documentsd) Preparation of the Quality Information for Drug Submission

for New Drug Approval: Biotechnological/Biological Products

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‘Similar biologics’ approved and marketed in India 

Product name

Active substance

Therapeutic area

Authorization date

Manufacturer

AbcixiRel abciximab AnginaCardiac ischemia

23 Apr 2013 Reliance Life Sciences

Alzumab itolizumab Psoriasis 27 Dec 2012 Biocon

Basalog insulin glargine Diabetes 2009 Biocon

Insulin insulin Diabetes mellitus 9 Aug 2011 Gland Pharma

CanMab trastuzumab Breast cancer 23 Oct 2013 Biocon

Filgrastim filgrastim Neutropenia 22 Oct 2013 Cadila Pharmaceutical

Choriorel chorionic gonadotrophin hormone r-hCG

Female infertility 22 Jun 2011 Reliance Life Sciences

Intalfa interferon alpha-2b

Carcinoid tumourChronic hepatitis BChronic hepatitis CHairy cell leukaemiaChronic myelogenous leukaemiaBCR-ABL positiveFollicular lymphomaMalignant melanomaMultiple myeloma

Apr 2007 Intas Biopharmaceuticals

Cresp darbepoetin alfa AnaemiaCancerChronic kidney failure

23 Mar 2010 Dr Reddy’s Laboratories

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Product name

Active substance

Therapeutic area

Authorization date

Manufacturer

Emgrast filgrastim CancerNeutropenia

16 Mar 2010 Gennova Biopharmaceuticals (Emcure)

Filgrastim filgrastim Neutropenia 5 Mar 2013 Lupin

Filgrastim filgrastim Neutropenia 3 Jun 2013 USV

Folisurge follitropin alfa(follicle stimulating hormone)

Female infertilitySpermatogenesis in men

14 May 2013 Intas Biopharmaceuticals

FostiRel follitropin beta(follicle stimulating hormone) 

Female infertility 30 Apr 2010 Reliance Life Sciences

Glaritus insulin glargine Diabetes mellitus Mar 2009 Wockhardt

MabTas rituximab LymphomaNon-Hodgkin’s Lymphoma

26 Feb 2013 Intas Biopharmaceuticals

Mirel reteplase (tissue plasminogen activator)

Myocardial infarction

2009 Reliance Life Sciences

Molgramostim Recombinant human granulocyte macrophage colony stimulating factor (molgramostim)

Neutropenia 14 May 2013 Zenotech Laboratories

Neukine filgrastim NeutropeniaHematopoietic stem cell transplantationCancer

Jul 2004 Intas Biopharmaceuticals

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Development process in IndiaDeveloped through sequential process to

demonstrate the similarity by extensive characterization studies

Reference biologic should be licensed in India

Testing of the similar biologic is generally less than that required for the reference biologic

Testing of the similar biologic should be sufficient to confirm acceptable levels of safety, efficacy & quality of product to ensure public health

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If reference biologic used for more than one indication :-

efficacy and safety of the similar biologic has to be justified

demonstrated separately for each of the claimed indications

justification depending on 3 factors

I. clinical experienceII. available literature dataIII. if same mechanism of action

involved in the different specific indications

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development and

characterization of cell

banks

stability of clone

cell culture/ fermentation purification

formulation

harvestprimary

packaging interactions

Flow chart of development

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Approval process

GMP standards

Quality tests

Pre-clinical testing to

GLP

Clinical testing to

GLP

Post marketing

safety

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Forces shaping the bio-similar market

Bio-simila

r marke

t

Rising health costs

Biologics patent expiries

Increase in the

occurrence of diseases

such as diabetes, cancer

Price of biologics

• Cost-effective alternatives to biologics reflects the growing demand for these kind of drugs.

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Factors supporting bio-similar market

Oligopolistic market

Less entry of competitors

Government initiatives to

encourage Bio-similars

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Bio-similar market in India Was estimated to be worth around $200 million

by Universal Consulting (an India-based market research firm) in 2008

Forecasted to reach $580 million by 2012Out of 130 companies in Indian

biopharmaceutical market , only 7-10 companies involved in recombinant product manufacture

Has immense expertise in gene manipulation and fermentation

Bioprocess development and cell-line development still in nascent stages

Only two companies have generated their own clones and cell lines

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Semi-regulated market Phase I-II trials not required for bio-similar approval

except in special cases total cost to develop a bio-similar ranges from $10 – 20

million which helps Indian companies to offer their products at a 25-40% cheaper price than the original biologics

Key challenges faced by the bio-similar companies in India-affordability

More than 85% of Indian population do not have any form of health insurance.

1% of the population has more than $20,000 income per annum

Even at 25-40% lower prices, the population that can afford such products is marginal

Therefore it is safe to say that comparison in the Indian market is not between an innovator brand and various biosimilar brands – but it is rather between traditional generic drugs versus bio-similar drugs.

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Specific company advancementsDr. Reddy’sReditux, the 1st bio-similar, a copy of

Rituximab manufactured by Dr. Reddy’s, has been available in India since 2007

Product portfolio:-I. filgrastimII. peg-filgrastimIII. Rituximab & Darbepeotin-αhave commercial presence in 13

emerging countries

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Lupin In a time period of 5 years have created & developed a total of 10 bio-similars in various stages of development among these are 8 potential blockbusters indicated for therapeutic conditions like Oncology,

Inflammation, Antivirals, Osteoporosis and Rheumatoid arthritis

The various highlights of 2013 are :-I. received marketing authorisation for its first oncology

product following the successful completion of its multi-centric, Phase III Clinical Trial in India

II. another long-acting oncology product is close to receiving marketing authorisation and has demonstrated excellent biosimilarity in Phase III Clinical Trials in India

III. 5 biosimilar products, including a basket of Blockbuster Monoclonal Antibodies and therapeutic Recombinant Proteins are in advanced stages of development, having successfully completed pre-clinical studies

IV. 3 process patents have been filed for 2 of these products

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CiplaAs recent as April 2013, the

company released its first bio-similar, Etanercept, used to treat rheumatic disorders.

Formed through a partnership alliance, the drug sold under the Etacept brand name will be manufactured by China-based Shanghai CP Guojian Pharmaceutical Co and marketed by Cipla in India, a note from Cipla said.

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WockhardtSeeking to partner in developed and

emerging markets for bio-similar portfolio

pioneering efforts in biotechnology led to successful launch of products in

IndiaI. Wepox (recombinant human

erythropoietin)II. Wosulin (recombinant human insulin)III. Glaritus (long-acting Insulin Glargine)

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ConclusionThe bio-similars market is in the nascent stage of

the industry life cycle with limited market and product development experience. However as patents expire, there is significant increase in market opportunities.

High initial investments are still a major barrier for new entrants.

Collaborations among large pharmaceutical companies with financial capabilities and specialty biotech companies with technical expertise are expected.

Integration of 3 key factors-marketing, research and development skills is the essential for success in the bio-similars market.

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A few biologics would be very attractive targets for bio-similar development due to their large revenues.

It is not possible to create a simplified general scientific pathway for developing bio-similars & therefore most products will have to go through a long, expensive and risky development process.

Getting an adequate market foothold for a bio-similar could be difficult when there is no added benefit over the innovator and insignificant cost savings.

It is highly unlikely that a formal regulatory pathway for bio-similars would benefit the small biotech industry.

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References

Web references- http://www.international.to/index.php?

option=com_content&view=article&id=52083:biosimilars-market-is-poised-to-reach-$2-0-billion-by-2018&catid=309:pitchengine&Itemid=446 (24.2.2014)

http://gabi-journal.net/the-future-of-biological-therapy-a-pathway-forward-for-biosimilars.html (24.2.2014)

http://www.lexology.com/library/detail.aspx?g=1ef6238a-310f-45d6-bba2-13eafd3ea1d0 (25.2.2014)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271516/ (25.2.2014)

http://www.reuters.com/article/2014/03/03/us-india-lupin-idUSBREA2216C20140303 (25.2.2014)

http://www.managingip.com/Article/3313982/India-Interesting-development-on-biosimilars.html (27.2.2014)

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http://www.thepharmaletter.com/article/india-now-making-moves-into-pharma-innovation (27.2.2014)

http://www.digitaljournal.com/pr/1736839 (27.2.2014)

http://www.marketwatch.com/story/global-biosimilars-market-2014-2018-2014-02-27?reflink=MW_news_stmp (27.2.2014)

http://www.ft.com/cms/s/0/a3d28626-9053-11e3-a776-00144feab7de.html#axzz2uugXR2kE (27.2.2014)

http://news.medill.northwestern.edu/chicago/news.aspx?id=227915 (28.2.2014

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http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe (2.3.2014)

http://www.gabionline.net/Biosimilars/General/Similar-biologics-approved-and-marketed-in-India (2.3.2014)

http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/default.htm (2.3.2014)

http://www.qps.com/whitepaper/QPS_CommercialWhitepaper_Biosimilars_Final_August2011_2.pdf

http://www.biospectrumasia.com/biospectrum/regulatory/1969/india-announces-biosimilar-guidelines/page/2#.UxgTw4VafTM

http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001811.jsp&mid=WC0b01ac058004d5c1(2.3.2014)

http://pharma.financialexpress.com/20120215/market04.shtml (3.3.2014)

http://www.lupinworld.com/biotechnology-research.htm (7.3.2014)

http://www.wockhardt.com/partnerships/collaborations-partnerships.aspx (7.3.2014)

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Text references- Tripathi K K, Shani S, Rathore A S. Guidelines on

Similar Biologics: Regulatory Requirements for Marketing Authorization in India.2012

Sekhon B S, Saluja V. Biosimilars : An Overview. Dove Press. 2011: 1:1-5

Balancing Innovation, Access, and Profits — Market Exclusivity for Biologics. New England Journal of Medicine.2009:361(917):1919

Kumar M: Biosimilars-Past, Present & Future. Regulatory Focus.2011:25-26

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