“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
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
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
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.
• 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.
• 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).
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.
Market overview
Regulatory issues
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).
• 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
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
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
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
‘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
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
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
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
development and
characterization of cell
banks
stability of clone
cell culture/ fermentation purification
formulation
harvestprimary
packaging interactions
Flow chart of development
Approval process
GMP standards
Quality tests
Pre-clinical testing to
GLP
Clinical testing to
GLP
Post marketing
safety
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.
Factors supporting bio-similar market
Oligopolistic market
Less entry of competitors
Government initiatives to
encourage Bio-similars
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
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.
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
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
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.
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)
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.
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.
References
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