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19Bhairav Bhushan A. et al . / International Journal of Biopharmaceutics. 2014; 5(1): 19-28.

e- ISSN 0976 - 1047 Print ISSN 2229 - 7499

International Journal of Biopharmaceutics

Journal homepage: www.ijbonline.com

BIOSIMILARS: GLOBAL SCENARIO AND CHALLENGES

Bhairav Bhushan A* 1, Saudagar Ravindra B 1, Gondhkar Sheetal B 2, Magar Dipak D 1,Vij Neha N 2

1Department of Pharmaceutical Chemistry, R.G.S. College of Pharmacy,

Sapkal Knowledge Hub, Anjaneri, Nashik, Maharashtra, India. 2Department of Quality Assurance Techniques, R.G.S. College of Pharmacy,Sapkal Knowledge Hub, Anjaneri, Nashik, Maharashtra, India.

ABSTRACTBiologics are a major growth driver for global pharmaceutical market. Biosimilars are those biologics which are

developed after patent expiration of innovator biopharmaceuticals. They are known as similar biologics, follow-on biologics, follow-on protein products, subsequent-entry biologics, bio-comparables, second-entry or off-patent biotechnology or multisource products in different countries. They require separate marketing approval since they are notgeneric versions of biologics. They are rather new molecules owing to a number of heterogeneities as compared to thereference innovator biologics. Hence, they require full documentation on quality, safety and efficacy. Several challenges inthe form of structural variability, immunogenicity, regulatory, etc. impede the way of growth of biosimilars. Structuralvariability results due to the complexity of structure of biologics. Immunogenicity is inherent to these products since they

are proteins. The lack of a robust regulatory framework poses a risk to patient safety. This article aims to highlight the biosimilars scenario on a global basis and it throws light on the regulatory guidelines of different countries. It also discussesthe major challenges involved therewith. It also considers some trends that promise the bright future of biosimilars.

Key words : Biosimilars, Biologics, Quality, Safety, Efficacy, Structural Variability, Immunogenicity, Regulatory.

INTRODUCTIONBiologics or biopharmaceuticals or bio

technologically produced drugs are a major growth driverfor the global pharmaceutical market. These aremedicinal products which contain proteins derived fromDNA technology and hybridoma techniques. Livingorganisms such as plant and animal cells, bacteria,

viruses and yeasts are used for the production of biologics (Misra M, 2012). Biologics are copies ofendogenous human proteins that are characterized bycomplex three-dimensional. These are high molecularweight compounds and are unique as they are

Corresponding Author

Bhairav Bhushan AE-mail: [email protected]

manufactured by using living cells. These extend humanabilities to fight diseases and are useful to mitigate evenincurable orphan diseases. Most biologics replace orsupplement a natural protein produced by the body.Hence they satisfy medical needs that were previouslyunmet by chemical drugs. The class of biologics israpidly growing and includes biological factors such as

cytokines, hormones, clotting factors, monoclonalantibodies, vaccines and molecules used for cell/tissue- based therapies. These drugs are far more complex withregard to their structure and mode of action thantraditional chemical drugs. The prediction andexploration of the exact mode of action of biologics isextremely difficult due to their complexity. For example,recombinant interferon interacts with nearly 100 genes.This poses many complex questions related to its study(Nowicki, 2007). Biosimilars are those biologics which

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emphasizes that its framework is generalized and it willonly apply to well-established biologics on market. Itseeks to rationalize clinical requirements majorly andstates that at least one clinical study will be necessary fora biosimilar to be approved. Its prime concern is thematter of immunogenicity. The WHO also requires theapplicants to include a plan for post-marketing safetyassessments in the application made for marketingapproval. However, some important debates likeinterchangeability or substitution and intellectual

property are unaddressed by WHO since these are notwithin its mandate as an advisory body (Brown C et al .,2009).

Biosimilars: Global Scenario

Europe

The first major player to develop a regulatorymodel for biosimilars is the European Union. A legal

basis for evaluation and approval of similar biologics inEurope was established with Directive 2001/83/EC of 6

November 2001, as amended by Directive 2003/63/EC of25 June 2003, which entered into force on 1 July 2003(called Annex I). Further developments were broughtwith the Pharmaceutical Legislation Review, in

particular Directive 2004/27/EC of 31 March 2004 thatamended Directive 2001/83/EC, to authorize theabbreviated approval of biologics that claim to be similarto an innovator product. This entered into force on 30October 2005 (Roger SD, 2006). However, the legislationleft a wide margin of discretion to the Committee forMedicinal Products for Human Use (CHMP) of theEMEA to develop product class-specific guidelines thatwould determine the extent of non-clinical and clinical

tests required (Som N, 2010). Hence in 2005, theEMEA/CHMP issued an overarching biosimilarsguideline along with two guidelines for consultation onthe quality, non-clinical and clinical issues andimmunogenicity to be considered for the development of

biosimilars (Nowicki M, 2007; Roger SD, 2006;Schellekens H, 2009). Since 2006, EMEA has beenimprovising and releasing guidelines covering severaldifferent types of recombinant proteins, including insulin,granulocyte-colony stimulating factor (G-CSF),somotropin and erythropoietin, as well as low-molecularweight heparins (Chu R et al ., 2009).

There are several biosimilar G-CSFs approved

in Europe: Biograstim/Filgrastim ratiopharm/Ratiograstim/ Tevagrastim (XM02); Zarzio and Nivestim etc (Table 1) (Gascon P, 2012).

The first generation of biosimilars was launchedusing the abbreviated pathway for similar biologicsestablished by EMEA. This marked the Biosimilars 1.0

period. Over the next several years improvingregulations, analysis, process development andmanufacturing capabilities and a global market spanningthe International Conference on Harmonization regions,

as well as the emerging markets will mark the beginningof the second era of biosimilars (Biosimilars 2.0). TheBiosimilar 1.0 period was characterized by the definitionof the initial framework. On the other hand, theBiosimilar 2.0 period will be marked by challenges in themanufacturing and clinical development of complex

products, global harmonization of standards and theincreasing demand for long-term safety and efficacy data(Miletich J et al ., 2011).

United States The Drug Price Competition and Patent Term

Restoration Act better known as Hatch Waxman Act of1984 (Nellore R, 2010), designed to deal with genericchemical drugs, was not intended to account for

biosimilar versions of biologics (Roger SD, 2006). A biosimilar approval pathway was established by theBiologics Price Competition and Innovation Act of 2009.It was signed into law as part of the Patient Protectionand Affordable Care Act of 2010 (Niederwieser D et al .,2011). On February 9, 2012, FDA issued three draftguidance documents intended to facilitate the submissionof marketing applications for biosimilars (Mahinka SP etal ., 2012):

Biosimilars: Questions and Answers RegardingImplementation of the Biologics Price Competition andInnovation Act of 2009 (Biosimilars Q&A) Scientific Considerations in DemonstratingBiosimilarity to a Reference Product (BiosimilarsScientific Guidance) Quality Considerations in Demonstrating Biosimilarityto a Reference Protein Product (Biosimilars QualityGuidance)

The FDA follows totality -of-the- evidenceapproach and reviews detailed information includingcomplete analytical testing, clinical immunogenicityevaluation, animal studies and human clinical trials.

The American market, including North Americaand Latin America, is expected to account for nearly35.3% of the total revenues in 2014. Biologics worth $25

billion are going to be off patent by 2016 and this willopen a pathway for the drug manufacturers to increasetheir market share, profit margins and reduce the medicalexpenditure of biosimilars (Pise S et al ., 2011).Epogen , Procrit , Eprex , Aransep are the

biosimilars currently available in the United States

(Schellekens H, 2009).

Canada Omnitrope was the first biosimilar of Canada. It

was approved even before the regulations were finalized.Canadas approach in terms of safety reflects that ofEMEA, but it takes a step ahead and addressesintellectual property debates. Canadas biosimilarf ramework is flexible in the biosimilar applicants choiceof which innovator biologic it uses as its reference;


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unlike the other major frameworks, the innovator biologic may be one that has not been approved andmarketed in Canada. This approach serves to encourage

biosimilar applicants. However, Health Canada(Canadas department of health) recommends utilizingthose innovator biologics that have been approved by

jurisdictions with which it has an establishedrelationship (Brown C et al ., 2009).

China China offers several advantages in biologics

manufacturing including a highly skilled workforce andrelatively well-established infrastructure and technologysystems. Biosimilars produced in China include productssuch as the interferon series, erythropoietin, colony-stimulating factor series, tumor neurosis factor, insulin,growth hormone, and interleukin-2. Most biosimilarshave been developed in Western countries such as theUnited States but China has come to the forefront due toincrease in its R&D capabilities (Minevich M et al .,2005).

JapanIn March 2009, the Japanese Ministry of Health,

Labour and Welfare issued guidelines for the approval ofBiosimilars (Niederwieser D et al ., 2011).

Australia

In June 2006, the Therapeutics GoodsAdministration adopted the European guidelines forregistration and approval of biosimilars (Niederwieser Det al ., 2011).

The Indian Front

The pre-1995 product patents do not apply inIndia due to the Trade-Related aspects of IntellectualProperty Rights (TRIPS) agreement. This meant that asmany as 48 biologics that were patented prior to 1995were marketable in India (Som N, 2010). Moreover, theinnovators had not sought patent protection for somedrugs in India, thereby creating a strong opportunity forIndian companies to influence the huge domestic market.This led to the Indian supply of biosimilars to othercountries where these products are not patented (NelloreR, 2010). Furthermore, the expiry of the patents of firstgeneration biologics like EPO, G-CSF, human growth

hormone, insulin and interferon gave companies theopportunity to enter a new, attractive market.

In India, Phase I-II trials are typically notgenerally required for biosimilar approval. These may becarried out in special cases. The establishment of

bioequivalence requires Phase III trials with a minimumof 100 patients. Therefore, the total cost to develop a

biosimilar in India ranges from $10 20 million. Thishelps Indian companies to offer their products at a 25-40% cheaper price than the innovator biologics. Also,

normally all biotechnological products are free fromIndian government price control except Insulin (Desai JP,2009).

At present, India is one of the leadingcontributors in the world biosimilar market. India hasdemonstrated the greatest acceptance of biosimilars,which is reflected from over 50 biopharmaceutical brandsgetting marketing approval (Langer E, 2008). The Indian

biotechnology industry had revenues of over U.S. $2 billion in 2006, 70% of which was biologics. Companieslike Biocon, Dr. Reddys Lab., Wockhardt, CiplaPharmaceuticals have already tapped the biosimilar

product opportunity (Mody R et al ., 2008). Biosimilarshave paved their way in India due to the regulatoryauthorities (Table 2) and regulatory guidelines cominginto force (Table 3) (Malhotra H, 2011).

[GLP - Good Laboratory Practices; DCGI -Drug Controller General of India; CT - Clinical Trial;GMP - Good Manufacturing Practices; DSMD - DataSafety & Monitoring Board; CTD - Clinical TrialsDossier; PMS Post Marketing Surveillance; PV -Pharmacovigilance; PSUR - Periodic Safety UpdateReport]

The Indian Pharmacopoeia 2007 containsmonographs for r -DNA Biotechnology Products ofTherapeutic Value including ErythropoietinConcentrated Solution , Granulocyte Colony StimulatingFactor, Human (Filgrastim), Interferon alfa-2concentrated solution, Streptokinase . The generalmonograph states, The product being a protein maycause immunological sensitization in the recipients andtherefore needs a high degree of characterization. Testingof the product for safety, identity, strength, quality and

purity are similar to those applied to other pharmaceutical products, although the tests themselves may require somemodification due to the pretentious nature of the activecompound. r -DNA derived products suffer from adanger of micro-heterogeneity in the expressed proteinand therefore require extensive process validation. Table 4 gives the biosimilar products in the Indianmarket (Undela K, 2012).

India Vs ChinaIndias current lead in biosimilars

manufacturing can be attributed to quality controlstandards and regulatory legislation. In addition, the high

English proficiency among recent Indian graduatesentering the field is also a contributor. India is thusstronger than China with respect to biosimilar market.However, with the evolving regulatory structure andlower wages of workers in China as compared to India,China is expected to overtake Indias position as theleader in biologic market by 2015 (Brown C et al ., 2009).

Challenges In The Way of Biosimilars

Various challenges impede the growth of


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biosimilars in the pharmaceutical market. It may be possible to tackle these problems but the effectiveness ofregulations is not assured since creating guidelines thatapply across all classes of biosimilars is difficult (RogerSD et al ., 2000).

Complexity of Biologics The biggest challenge in the development of

biosimilars arises from the fact that biologics are morecomplex than small molecule and chemically synthesizeddrugs. Therefore, in contrast to traditional small -molecule generics they are similar but not identical tothe innovator biologic.

Generic drugs are chemically andtherapeutically equivalent to branded, original chemicaldrugs whose patents have expired. There are variousdifferences between chemical drugs and biologics alongwith those between chemical generics and biosimilars(Table 5) (Sekhon BS et al ., 2011). Generic drugs areapproved through a simplified registration procedure, theabbreviated new drug application (ANDA), with thedemonstration of bioequivalence. However, the samestandards cannot be applied for the development andevaluation of biosimilars.

Variability in characteristics of biosimilarsThe molecular weight of biologics is 100 to

1000 times larger than small molecule chemical drugs.They possess fragile three-dimensional structure which isdifficult to define by analytical tools (Roger SD,2006).The characteristics of biologics are largelydetermined by their manufacturing process. Differentmanufacturing processes use different cell lines, protein

sources, extraction and purification techniques, whichresult in heterogeneity of biologics. Even minordifferences in cloning, fermentation or purification alter

properties of biologics. It may be possible to mimic theinitial amino acid sequence (primary structure), butanalysis of structure reveals local folding (secondarystructure) and subsequent global folding (tertiarystructure). This occurs via various hydrogen anddisulphide bonds. Oligomerization and modification ofthe protein primary sequence or glycosylation patterns isalso observed (Roger SD, 2006; Schellekens H, 2009).

Some biologics also exhibit quaternary structure, whichis the stable association of two or more polypeptide

chains into a multi-subunit structure, and this may furtheralter activity, duration of action, stability, pharmacokinetics, safety, immunogenicity and other properties (Roger SD, 2006).

Specific manufacturing processes, validationand full characterization of proteins are generally acompanys intellectual property and it becomes difficultfor another manufacturer to reproduce a biologic similarenough to the original innovator product, based only onthe patent or published data (Blackstone E et al ., 2012). A

classic example to illustrate that the safety profile of a biosimilar will not be identical to that of the reference product is the biosimilar growth hormone Valtropinethat has different precautions and warnings than itsreference product Humatrope. This may be aconsequence of use of different cell lines (Undela K,2012). All the heterogeneities between biosimilars and innovator

biopharmaceutical have an impact on patient safety.

Shortcomings of characterization tools

Characterization of biosimilar product viaanalytical techniques is possible. However,

physicochemical properties are assessed by techniqueslike MS in which extraction is required. This could

possibly induce a change in physicochemical or structural properties of the material and hence influencecomparability with reference innovator biologic (Cai XYet al ., 2013).

Also , it is not always feasible to assess thedrugs potency with bioassays. Moreover, bioassaysthemselves dont have a universal stand ard and this leadsto further variability. Due to lack of a reference standardfor bioassays and the variability in binding assay resultsno clear guidelines can be set (Roger SD, 2006). Hence,there is also a lack of appropriate investigative tools.

Resources for fulfilling Regulatory requirements

It is claimed that the process is the product,hence biosimilars can never be bio-identical with theinnovators biologic (Roger SD, 2006). Thus, to obtainmarketing authorization, the biosimilar should beconsidered in general as a new product that needs full

documentation concerning quality, safety and efficacy.Small proteins such as insulin and calcitonin, which havevery well-known properties and have been produced formany years, might be exempt from this rule (SchellekensH, 2004). The registration of biosimilars requires moredata than for generics, and manufacturers have todemonstrate efficacy and safety via extensive pre-clinicaland clinical studies. Data gathered from assessment ofkey similarities and differences between innovator

biologic and biosimilar must also be submitted (Peres BCet al ., 2012). Thus the registration of biosimilars is acostly and time-consuming process. Furthermore, theEMEA requires also post-marketing safety studies to

observe immunogenicity and to establish rigorous pharmacovigilance programs (Schellekens H, 2009). Thisincreases resources required.

ImmunogenicityImmunogenicity is the capability of a specific

substance to induce the production of antibodies in thehuman body. All biologics demonstrate a greater capacityto elicit such an immune reaction because they are

polypeptides or proteins. In many patients, such a


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response does not lead to any clinical consequences.However, there is potential for general immune reactionslike allergy and anaphylaxis. In addition, they may causereactions which lead to a loss of effect from the medicineor rarely reactions which cause an enhancement ofactivity. The most impressive complications of antibody

production arise when the antibodies cross-react with anendogenous factor that has a unique and important

biological function, thus disturbing body homeostasis(Schellekens H, 2004).

Immunogenicity may be influenced by factorsrelating to the drug itself e.g. manufacturing process andformulation, and also by factors related to the patient,disease or treatment e.g. route of administration ordepressed immune response in cancer patients (Brown Cet al ., 2009). Immunogenicity needs to be monitoredduring every stage of development of biosimilars andthroughout its life using bioassays. It should be noted thatresponses are highly individual and that bioassays are notstandardized. Different laboratories use their own assayformat, and no international standards are available.Sampling time can also influence results because the

product in circulation can mask the presence ofantibodies (Schellekens H, 2004).

Substitution or interchangeabilitySubstitution of chemical drugs by generic

versions is a common practice followed by pharmacists.It must be avoided in the case of biologics (NiederwieserD et al ., 2011). Biosimilar products are never identicaland immune responses against them are highlyunpredictable (Nowicki M, 2007; Roger SD et al ., 2007)hence, selection of a substitute must be done carefully.

Intellectual property issuesBiosimilars raise two major problems associated

with patents. The first relates to the actual R&D processleading to the creation of a new drug and the second tolitigation. The fact that a biosimilar will not be requiredto be the same as the innovator biologic potentiallyallows biosimilar companies to design around relevant

patents, so that they create a product that is (1)sufficiently similar to rely, at least to some extent, on themarketing approval of the innovator biologic, yet (2)sufficiently different to avoid patent infringement. Thus,

biosimilars could reach the market well ahead of the

expiration of patents belonging to innovator biologicsand at much considerably lower costs. As a result, patent protection may not be as robust for biologics as it is forsmall-molecule chemical drugs. Also, a biologic can holdseveral patents, for example, not only on the activeingredient and route of administration, but also on thedevelopment and manufacturing technology. Hence,disputes over patent infringement may become evenmore complicated. (Chu R et al ., 2009).

Counter-steps of innovators

Chemical generics lower drug prices by as muchas 90 per cent. On the other hand, biosimilars are only 10to 20 per cent less than the branded biologics owing tothe expenses. Therefore, an innovator biologic couldreduce its price by a fairly small amount, perhaps 10 to20 per cent and this will discourage buyers fromswitching to the biosimilar (Blackstone EA et al ., 2012).

Efforts to Pave the Way For Biosimilars Nurses, hospital pharmacists, dispensing

pharmacists, prescribers, and patients must all be awareof and educated about biosimilar for avoidingsubstitution or interchangeability related problems and tomake use of cheaper versions of biologics. Cliniciansrequire comprehensive information on biosimilars tomake knowledgeable treatment decisions. It is a must for

patient safety (Roger SD et al ., 2007; Sekhon BS et al .,2011). Drug price reductions may be an important factorto consider in the developing countries, whereas patientsafety and brand loyalty may be deciding factors indeveloped countries (Roger SD et al ., 2007).

Pharmacovigilance as a solution

All European pharmaceutical companies arelegally required to monitor the use and effects of all theirmedicines. They must have systems in place to detect,assess, understand, communicate and prevent any adversereactions or any other medicine related problem. Thescience and activities of these processes are known asPharmacovigilance (Brown C et al., 2009). As a part ofthe pharmacovigilance activities, the type and level ofimmune response should be examined after the product is

authorized and marketed (Schellekens H, 2004). Thisforms a component of a robust risk management plan.

EMEA requires biosimilars to have a uniqueINN to facilitate prescribing and dispensing and also toaid in precise pharmacovigilance (Nowicki M, 2007).

Biosimilar manufacturers should exhibit a patient-focused commitment to upholding the higheststandards. Biologics manufacturers should not adoptidentification mechanisms that risk confounding

pharmacovigilance data with those of othermanufacturers. Reliable and rapid tracing of adverse drugreactions (ADRs) to the actual biologic product is a must.Biologics have a unique risk profile compared with

traditional pharmaceuticals since ADRs can occur as aresult of the interaction of specific structural differenceswith the physiology of individual patients. Since thesestructural differences can be process-specific, evenhighly similar biologics could diverge in terms of

prevalence or severity of ADRs. Without traceability,adverse safety outcomes related to differences in qualitycould go unrecognized or undetected, thus increasing thelikelihood that emerging adverse events would not berecognized as being uniquely related to a particular


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Table 3. The regulatory pathway for approval of biosimilars in India

Product development Approval needed from Institution al Bio-safety Committee (IBC) Approval needed from Department of Biotechnology (DBT)

Animal toxicity studies Protocol to be designed as per schedule Y, approved by DBT Study need to be conducted in GLP accredited laboratories Report need to be approved by DBT

Clinical trail Protocol need to be approved by DCGI (followed by DBT approves the toxicitystudy report) Manufacturing license is needed for CT batch manufacturing (along with WHOGMP certificate) The protocol need to be appr oved by Institutional Ethics Committee Any deviation need to be approved by DCGI and DSMB

Marketing and manufacturing license CT report to be submitted to DCGI The dossier (in CTD format) need to be approved by DCGI Manufacturing license shou ld be issued after inspection of the facility

Post approval commitments Mandatory PMS (at least for 4 months) PV study (throughout) Every 6 months safety reporting to DCGI for first 2 years (PSUR) Any process change need to be approved by DCGI

Table 4. Biosimilar products in India

Biosimilar Company Product Name Year of LaunchInsulin Wockhardt

BioconShreya Life Sciences

WosulinInsugenRecosulin

200320042004

Erythropoietin Hindustan AntibioticsEmcureWockhardtRanbaxyIntas PharmaceuticalsShantha Biotechnics

HemaxEpoferWepoxCeritonEpofit & ErykineShanpoietin

200020012001200320052005

Hepatitis B vaccine Shantha BiotechnicsBharat BiotechPanacea BiotecWockhardtSerum Institute of IndiaBiological E

Shanvac BRevac BEnivac HBBiovac-BGene Vac-BBevac

199719982000200020012004

Granulocyte colonystimulating factor

Dr Reddy s LaboratoriesIntas Pharmaceuticals

Grastim Neukine

20012004

Streptokinase Bharat BiotechShantha BiotechnicsCadila Pharmaceuticals

IndikinaseShankinaseSTPase

200320042004

Interferon alpha-2b Shantha Biotechnics Shanferon 2002Rituximab (MAb) Dr Reddy s Laboratories Reditux 2007Anti- Epidermal Growth Factor (MAb) Biocon BioMAB-EGFR 2006

Table 5. Differences between small chemical drugs and BiologicsSmall-molecule drug BiologicsProduct related differences Produced by chemical synthesis Low molecular weight Well -defined physiochemical propertiesStable Single entity, high chemical purity, purity standardswell establishedAdministered through different routes of

Biotechnologically produced by host cell lines High molecular weight Complex physiochemical properties Sensitive to heat and shear (aggregation) Heterogeneous mixture, broad specifications which maychange during development, difficult to standardizeUsually administered parenterally


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administrationRapidly enters systemic circulation through bloodcapillariesDistribution to any combination of organ/tissue Often specific t oxicityOften non -antigenic

Larger molecule primarily reach circulation via lymphatic system, subject to proteolysis during interstitial andlymphatic transitDistribution usually limited to plasma and/or extracellular fluidMostly receptor mediated toxicity Usually antigenic

Manufacture related differences Completely characterized by analytical methods Easy to purify Contamination can be generally avoided, is easilydetectable and removableNot affected by sli ght changes in production processand environment.

Difficult to characterize Lengthy and complex purification process High possibility of contamination, detection is harder andremoval is often impossible Highly susceptible to slight changes in produc tion processand environment

Fig 1. The timeline for development of biosimilar

CONCLUSIONBiologics will become an important part of thefuture healthcare landscape. Biologics and properlyregulated biosimilars will increasingly become available.The development of biosimilars represents a significantopportunity for generic firms interested in entering themarketplaces for biotechnologically produced drugs.Without the necessity of undertaking costly full-scaleR&D activities, they can manufacture and marketrecombinant proteins. However, success in the

biosimilars industry will require significant capitalinvestment and in-house experience. Biosimilarsmanufacturers have to face higher costs for

manufacturing, clinical development, registration and product marketing compared to classic generics.

The establishment of a globally harmonizedregulatory framework is important. India and Argentinacurrently apply standard generic drug authorization

provisions to biosimilars. On the other hand Australia,Bulgaria, Canada, Chile, China, Croatia, EuropeanUnion, Israel, Japan, Mexico, Serbia, Switzerland,Taiwan, Turkey and Ukraine have already establishedspecial provisions. Egypt, New Zealand, Oman, Panamaand Russia do not permit any application for biosimilars.The insufficient power supply and storage conditions inIndia pose a big challenge to biosimilar stability.Moreover, the market for resale of expired drugs withcompromised safety and efficacy is mushrooming inIndia. This may be a safety concern for biosimilars.Developing specific guidelines is important for approvalof biosimilars in India. Various aspects like quality of the

product, pharmacovigilance, immunogenicity, etc. must be touched in the guidelines with special emphasis on

immunogenicity studies. Some outstanding issues likenaming, substitution and labeling need to be resolved(Schellekens H, 2009).

A quality biosimilar is that which exhibits thesame concentration and equivalent potency to, thereference biologic. This assures that the biologic providesa similar clinical effect at a given dose. This will bringchoices to patients, prescribers and payers in manymarkets without asking them to make trade-offs betweencost and benefit risks of a biologic (Miletich J et al ., 2011). For healthcare purchasers and national pricing andreimbursement authorities, biosimilars offer anequivalent and less expensive alternative to reference

biologics. This means that more patients can be treatedwithin the same limited budget.

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