EGA Handbook on Biosimilar Medicines

7/25/2019 EGA Handbook on Biosimilar Medicines

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EGA HANDBOOK ON BIOSIMILAR MEDICINES

EUROPEAN GENERIC

MEDICINES ASSOCIATION


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CONTENTS

Foreword 1

Executive Summary 2

Why are Biosimilar Medicines Important? 4

Context 6Why has the term Biosimilar Medicine been chosen? 8

Science and Technology behind Biosimilar Medicines 8

Regulation of Biosimilar Medicines 12

Access to Biosimilar Medicines 15

Evolving Landscape of Biosimilar Medicines 17

Further Information 18

Reviewers 18

Contributors 19

Glossary 20References 22

Acronyms and Abbreviations 24


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FOREWORD

The first fivebiosimilar medicineswereapproved for use in Europe in 2006and 2007.

This short guide is intended to be thereference source for those who need tounderstand what these new medicinesare; why they are becoming moreimportant; their benefits and questionsraised by this emerging type of vitalmedicine.

It will be particularly useful to:

Patients and PatientAdvocacy Groups

Clinicians and Prescribers

Retail and Hospital Pharmacists

Those responsible for fundinghealth and healthcare on aregional or national basis

National pricing andreimbursement authorities

Politicians and advisers

Policy makers

This handbook provides the backgroundto the emergence of biosimilarmedicines, and the clinical and healtheconomic benefits they offer to patients,clinicians and healthcare providers.

It describes the science and technologybehind biosimilar medicines; how theyare produced and regulated, and alsocovers the questions surroundingthem, namely:

terminology

quality, safety and effi cacy

comparability

non-clinical tests andclinical trials

pharmacovigilance

immunogenicity

access to medicines

identification and traceability

interchangeability andsubstitution

The handbook focuses on the currentsituation in the European Union (EU)and concludes with a summary of thedevelopments likely to occur in thenear future.

A glossary of terms, highlighted in boldin the text, and a list of acronyms orabbreviations are also provided at theback of the handbook.

On behalf of the EGA Board of DirectorsI believe that this handbook will greatly

enhance the knowledge about biosimilarmedicines and understanding of theirpublic health contribution.

I thank you for your time in readingthis document.

Greg Perry, Director General

EUROPEAN GENERICMEDICINES ASSOCIATION


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EXECUTIVE SUMMARY

Generic medicineshave made a majorcontribution to affordable and accessiblehealthcare for over 20 years, saving theEuropean Union (EU) alone an estimated20 billion annually.

By 2010 biopharmaceuticals, which aredefined for the purpose of this handbookas medicines made by or derived fromliving organisms using biotechnology, areexpected to grow 12-15% per year.1

They represent one of the fastest-growing segments of the pharmaceuticalindustry, and there are more than 200of them on the market today. Some 300more are being investigated inclinical trials.2

Biopharmaceuticals can now also beproduced by manufacturers other thanthe originator when the relevant patentshave expired. These new biotechnologicalmedicines are most commonly known asbiosimilar medicines, which will be theterm used throughout this handbook.In other texts they may be namedsimilar biological medicinal products,biosimilars, follow-on biologics orbiogenerics. Biosimilar medicines aretherefore a subset of biopharmaceuticals,with comparable safety and effi cacy

to originator reference medicinalproducts. The main difference betweenthe two is that biosimilar medicines willbe less expensive.

To gain approval, biosimilar medicineshave to demonstrate that they are assafe and effective as the originatorreference product. Biosimilar medicinesare evaluated for their similarity and

comparabilitywith the referenceproduct. This evaluation is customisedto each biosimilar product and theactive substanceit contains, togetherwith the methods used for developmentand the clinical use of the product.One key aspect to be considered is thevariation of potency and purity of theproduct which should be within thelimits displayed by the reference product.The biosimilar development processuses the latest analytical and clinicaltechnologies, including some that mayhave not been available to assess thereference product at the time it wasfirst approved.

Once the medicine is approved,specific monitoring is required forbiopharmaceuticals to assure continuedsafety and effi cacy. In addition to thespecific monitoring, data is collectedthrough pharmacovigilance activities.The data collected is used to prepareperiodic safety update reports (PSURs).These reports review the risk-benefit of

medicines, at frequent intervals after theproduct is first approved and marketed.Pharmacovigilance is not specific tobiosimilar medicines but applies to allmedicinal products.

Biosimilar medicines now offer a majoropportunity to provide greater accessto affordable healthcare for severallife-saving medicines, at least equallysignificant to the emergence of generic

medicines over the past two decades.Biosimilar competition resulting in just a20% price reduction on five off-patentbiopharmaceutical medicines couldsave the EU over 1.6 billion per year.Since 2004, there has been accelerationin this new field of pharmaceuticaldevelopment, with the first fivebiosimilar medicines gaining Europeanregulatory approval in 2006 and 2007.

Biosimilar medicines are approved bythe European Commission (EC) through

the European centralised procedure,which is overseen by the EuropeanMedicines Agency (EMEA). The termbiosimilar medicine is derived fromthe EU legislation governing thisapproval process. As is the case for allmedicines, European regulations andguidelines are in place to ensure thequality, safety and effi cacy of biosimilarmedicines, and also to avoid unnecessaryclinical testing. Quality, in this context,means the controls and standards forall manufacturing, preparation and

processing of the product.


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Healthcare providers can now work withclinicians and pharmacists to improvethe availability and affordability ofthese important medicines to morepatients, confident in the knowledge

that they have been scientificallyassessed by the EMEA and approved bythe European Commission.

Biopharmaceuticalsmade by or derived from livingorganisms using biotechnology

Originatorbiopharmaceuticals

used as reference medicinalproducts for the development of

biosimilar medicines

Biosimilar medicinescan now be made available bymanufacturers other than the

originator companies when therelevant patents have expired

Figure 1: Overview on biopharmaceuticals


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WHY ARE BIOSIMILARMEDICINES IMPORTANT?

For patients:The regulations governingbiosimilar approval, developed throughextensive consultation and scientific

peer review, ensure the quality, safetyand effi cacy of biosimilar medicines.These are now an emerging source ofaffordable medicines for more patientswho have some of the most diffi cultto treat diseases. Manufacturers otherthan the originator companieshave thescientific capability to produce biosimilarmedicines, which can take place whenthe relevant patents of the originatorreference products have expired.Information about specific biosimilarmedicines is available from a number

of sources, including the EMEA, toenable patients, together with theirdoctor and pharmacist, to have accessto the relevant data on the use of thesemedicines. Patients can have confidencein them because they are approved bythe same regulatory organisation - withthe same scientific rigour, using the sameregulatory systems as the comparableoriginator products.

For clinicians: Biosimilar medicines,evaluated scientifically by the EMEA andapproved by the European Commission,

must demonstrate that they have asimilar safety and effi cacy profile as thereference product. Possible concernsabout immunogenicity, which applies toall biopharmaceuticals, both originatoras well as biosimilar medicines, areaddressed through the pre-clinicaland clinical development programmesprior to approval, pharmacovigilanceafter approval and if appropriatethrough Post-Authorisation SafetyStudies (PASS). Applications for allnew biopharmaceuticals, including

biosimilar medicines, must also includea Risk Management Plan(RMP) in theEU which shows that the company hasassumed the responsibility and liabilityfor its medicines, ensuring that allappropriate actions and surveillance willbe taken, as considered appropriate andnecessary by the EMEA.

Biosimilar medicines offer an affordablealternative to reference products,allowing greater access to thesemedicines for more patients.

For pharmacists: Pharmacists havea leading role in ensuring that themost appropriate medicines are made

available to the right patients in theright way, and at the right time. A primeresponsibility is the evaluation andsupply of new medicines within theirnational regulatory and reimbursementframework.

Biosimilar medicines are an emergingsource of affordable biopharmaceuticalswhich pharmacists can critically appraise,referring to data published on the EMEAwebsite, in order to support clinicaldecisions and health provider (payer)expectations. The very robust regulatorysystems now in place in the EU allow fullconfidence in biosimilar medicines.


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For healthcare purchasers and nationalpricing and reimbursement authorities:Biosimilar medicines offer an equivalent

and less expensive alternative toreference products. This means that morepatients can be treated within the samelimited budget or real savings may beused to fund other treatments, ifso chosen.

For politicians, advisers and policymakers:The EMEA is the regulatorybody that examines the data for eachbiosimilar medicine on a case-by-casebasis. The European Commission grants apan-European marketing authorisationbased on the EMEA positive scientificopinion. The EMEA is also responsible forthe development of guidelines related tobiosimilar medicines. These are developedin discussion with many stakeholdersincluding industry, clinicians and patientadvocacy groups. Biosimilar medicinesprovide a means of introducingcompetition into the biopharmaceuticalmarket, which will allow more flexibilityfor the uptake of new innovativetherapies. The EMEA and the EuropeanCommission provide the first and finalarbiter of quality to ensure that patientsafety is not compromised.


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CONTEXT

Healthcare is high on the agenda ofevery Member State in the EU. Peopleare living longer, but also showing anincreasing prevalence of many seriousand long-term conditions such asheart disease, cancer, and diabetes. Themedical treatment of these patients hasto be provided within a finite budgetof healthcare resources, so individualgovernments are developing policies andmechanisms to try and gain the bestpatient benefit, while controlling costs.

Medicinesare a valuable component ofhealthcare, and a significant element ofhealthcare expenditure. The latest figuresfor the EU show that medicines accountfor an average of around 18% of total

healthcare costs, rising for exampleto 38.5% in the Slovak Republic.3Healthcare providers across the EU aretherefore finding ways to reduce thecost of medicines including measures toincrease generic competition.

In essence, there are two types ofmedicine used to treat human disease.Conventional chemical medicines -called pharmaceuticalsin this handbook and biopharmaceuticals, which aremedicines made by or derived from living

organisms using biotechnology.

Conventional Pharmaceuticals -Generic Medicines

Generic medicines are less expensiveversions of conventional pharmaceuticals

which have made a major contributionto affordable and accessible healthcarefor over 20 years, saving the EU alonean estimated 20 billion per year. Theyare used very widely in the EU in a largenumber of therapeutic areas includingcancer, cardiovascular disease, diabetes,gastro-intestinal disorders, pain, asthmaand infections.

Generic medicines are available ataffordable prices to patients andhealthcare professionals after the patent

protection period of the originatorproduct has expired. As a result, morepatients can be treated or savings canbe used to fund other therapies, if sochosen. In addition to price competition,the introduction of generic medicinesalso stimulates the development of newinnovative medicines.

Generic medicines contain activesubstances whose safety and effi cacyare well established. New clinical trialsare therefore usually not required fortheir approval. This approach is also in

line with ethical principles not to repeatunnecessary tests on animalsand humans.

Generic medicines must provebioequivalencewith the referenceproduct which broadly means that theyneed to demonstrate that the same doseof the generic and reference product

behave in the body in the same way.Furthermore generic medicines mustmeet the same quality standard asreference products. Quality meansthe controls and standards for allmanufacturing, preparation andprocessing of the product. They areconsequently therapeutically equivalentto and therefore interchangeable withthe reference product in the respectiveindications.

Biopharmaceuticals -Biosimilar Medicines

Biopharmaceuticalshave been availablefor over twenty years. They fall intodifferent classes:

Hormone products e.g. growthhormone for growth hormonedisorders, erythropoietin for theanaemiaof kidney disease, andinsulin for diabetes

Immunomodulators e.g. beta- interferon for multiple sclerosis

Monoclonal antibodies(MABs) e.gtrastazumab for breast cancer

Blood coagulation modulators e.g.factor VIII and IX for blooddisorders such as haemophilia

Enzymes e.g. for the treatment ofmetabolic disorders such asGaucher disease

Vaccines


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The development process forbiopharmaceuticals is a complex one. Thesciencebehind this process is describedmore fully in the next section.

Manufacturers other than the originatorcompanies have the scientific capabilityto produce biopharmaceuticals when therelevant patent has expired. In Europe,this new category of medicines is calledbiosimilar medicines, or sometimes thelonger legal term similar biologicalmedicinal products is used. An EUbiosimilar medicine has been comparedto, and has demonstrated that it matchesthe reference product in terms of quality(how it is manufactured), safety (e.g.the adverse reactionsthat can occur)

and effi cacy or effectiveness (its desiredeffect in the body). Details on approvedbiosimilar medicines are availablethrough European Public AssessmentReports (EPARs)4,5which are publishedon the EMEA and the EC websites.

Biosimilar medicinesare a new sourceof affordable biopharmaceuticalsfor more patients who have some ofthe most diffi cult to treat diseases.As a consequence of the firstbiopharmaceuticals reaching theend of their patent life, there hasbeen acceleration in this new field ofpharmaceutical development since 2004.

Table 1: Timelines for emergence of biosimilar medicines:

The first patents protecting biopharmaceuticals expired 2001

The notion of biosimilar medicine or the concept of biosimilarity was

introduced into EU legislation in June 2003 and further developed with

the adoption of the EU Pharmaceutical Review on 31 March 200462003/4

EMEA receives first three biosimilar medicine applications7 2004

The EMEA published an overarching guideline describing the concept of

biosimilar medicine and the basic principles to be applied82005

The EMEA finalised two guidelines for biosimilar medicines (quality and

non-clinical / clinical issues)9,102006

EMEA produced four product specific guidelines covering Granulocyte

Colony Stimulating Factor (G-CSF), insulin, growth hormone and

erythropoietin) outlining non-clinical/clinical requirements for

comparability of biosimilar medicines11,12,13,14

2006

EMEA receives three more applications for biosimilar medicines7 2006

European Commission approved the first two biosimilar medicines,

Omnitrope and Valtropin, which are both human growth hormone

products for the treatment of growth hormone deficiency15

2006

Twelve applications for initial evaluation of biosimilar medicines have

been received by the EMEA162007

The European Commission, on the basis of the positive scientific

opinion by the EMEA, approved three biosimilar medicines (based on

one development): Binocrit(Epoetin alfa) from Sandoz GmbH, Epoetin

alfa Hexal (Epoetin alfa) from Hexal Biotech ForschungsGmbH andAbseamed (Epoetin alfa) from Medice Arzneimittel Ptter GmbH & Co

KG15. (These are all erythropoietins)

2007

EMEA published a Questions and Answers document on biosimilar

medicines (similar biological medicinal products)172007

The EMEA adopted positive scientific opinions for the biosimilar

medicinal product Silapo (Epoetin zeta), from Stada Arzneimittel AG,

and Retacrit (Epoetin zeta), from Hospira Enterprises B.V.18These are

erythropoietins. The European Commission approvals follow the positive

EMEA opinion.

2007

More biosimilar medicine applications and approvals are anticipated2008-

2010


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WHY HAS THE TERMBIOSIMILAR MEDICINEBEEN CHOSEN?

The European Commission and theEMEA chose the term similar biological

medicinal product more often calledbiosimilar medicine to reflect theapproach of approving a biologicalmedicine which is similar to an alreadyauthorised reference biological medicine.Typically a more extensive and veryexpensive development programme,including more registration data,is required for biosimilar medicinescompared to generic medicines todemonstrate that the therapeuticperformance of the biosimilar medicineis comparable to the reference product.

This explains why the term biosimilarwas chosen over the term biogeneric.

All biopharmaceuticals are inherentlyvariable due to the fact that they are

produced from living organisms. Thisvariability exists within batches, frombatch to batch, and when productionprocesses are improved or changedor differ between manufacturers. Thevariability of biopharmaceuticals isgreater than that typically observedfor conventional pharmaceuticals andapplies to originator biopharmaceuticalsas well as to biosimilar medicines. Thisalso explains why the term bio-identicalcannot be used.

Biosimilar medicine is (to date) a termderived from the nature of the medicineand from the EU regulatory and legalroute for approving these medicines,rather than an agreed terminology thatwill be used globally.

SCIENCE AND TECHNOLOGYBEHIND BIOSIMILARMEDICINES

Biopharmaceuticals contain muchlarger moleculesthan conventional

pharmaceuticals, and each has a setof characteristics naturally subjectto some variability. They are usuallyproteinsor polypeptides. Thevariability includes the shape of themolecule (folding) and the type andlength of any sugar or carbohydrategroups that may be attached to it(glycosylation).

All biosimilar medicinesare biopharmaceuticals.Biopharmaceuticals, includingbiosimilar medicines, are producedin, and isolated from, livingorganisms. The end product hasto be purified from the thousandsof other biomolecules present ina living cell or living organism,therefore the production processrequires sophisticated and validatedtechnologies, and the pharmaceuticalcompany developing the biosimilarmedicine needs to have theassociated scientific capability.

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How are biopharmaceuticalsdeveloped?

Biopharmaceuticals are developedusing a variety of mechanisms,but representation of a standardbiotechnological process is shown inFigure 2.

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Figure 2: Technical development and production of a biopharmaceutical

Cell cultures / strains

Seed cultures

Fermentation

Harvesting

Product enrichment

Purification

Active Ingredient


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The development goals for bothreference and biosimilar medicinesare safety, quality (of production),reproducibility and effi cacy.

The development of a biosimilarmedicine is based on at least ten yearsof clinical and regulatory experiencewith the reference product. This wealthof knowledge provides information todevelop and produce the biosimilarmedicine, and defines the testing neededto assure biosimilarity with the referenceproduct.

Biosimilar production starts either withthe cloned cell-line (copies of host cellswith the target gene in place) or the seedculture ready to be fermented (Figure 2).The cell-line or culture can be developedby the manufacturer; purchased fromanother company or developed inpartnership with a company who has therequired expertise and capability.

In this way manufacturers of biosimilarmedicines can reduce the time fordevelopment by up to two yearsin comparison to the originatormanufacturer (Figure 3).

0 1 2 3 4 5 6 7 8

Step 1: Copy the host cells

Step 2: Make the cell-banksPurify the bio-factory

Step 3: Process DevelopmentFermentationPurification

Step 4: Scale-up

Step 5: Comparability TestingAnalytical (1 year)Clinical (up to 3.5 years)

1-1.5 years

1-1.5 years

3.5-4.5 years

Years

Each biosimilar medicine has a validatedprocess of development to ensure thatit matches its reference product interms of quality, safety and effi cacy. Adevelopment programme may include:

A thorough characterisation programme to compare the purity

of the potential biosimilar medicine with the reference

product. This is done using a large series of different state-of-the-art analytical tests, as no single

method can characterise allaspects of a product.

If there are significant differencesfound on analyses, thedevelopment process is modifieduntil the product generated has aprofile which matches the profileof the reference product.

This modification continues atevery stage of the development

process so that the final biosimilarmedicine matches the referenceproduct by every criterionrequired by the EMEA when thefile is submitted for assessmentand marketing approval.

The stages in development of a biosimilarmedicine are summarised in Figure 4.

Regulatory authorities have theexpertise and the data to decide whethercomparability has been demonstratedbetween a biosimilar medicine and itsreference product.

The cost of developing a biosimilarmedicine is at least ten times greater

than for generic medicines. These costsdo not include building specialisedmanufacturing plants or very expensivePost-Authorisation Safety Studies (PASS).

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Figure 3: Timeline for development of a biosimilar medicine


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How are biopharmaceuticalsproduced?

Both originator reference products andbiosimilar medicines are made undercarefully controlled conditions toensure the products are consistent, andmanufactured to the required quality.This is known as Good ManufacturingPractice (GMP).

In the European Union, GMP inspectionsfor all biopharmaceuticals (bothoriginator and biosimilar medicines) arecoordinated by the EMEA and performedby National Regulatory Agencies. Thereare three levels:

Routine GMP inspections ofmanufacturing sites to ensure thatmedicines are produced safelyand correctly

Pre-Approval Inspections(PAI)for GMP compliance prior to

the approval of new medicinesfor marketing if there are specificissues identified during theapproval process

Unannounced inspections

On 1 May 2007 the EMEA launched anew database designed to facilitate theexchange of information on compliancewith GMP within the European medicinesnetwork. The database, called EudraGMP,can be accessed by national competentauthorities, the European Commissionand the EMEA.

Biosimilar medicines are made byspecialist organisations. They may be adedicated but separate part of a largepharmaceutical company, a stand-alonebiotechnology company, or a partnershipbetween the two, which has benefits interms of reducing development costs.The development and manufacture ofthese products is a complex field whichis expensive, requires particular expertiseand carries a degree of commercial risk.

Not all biopharmaceuticals willnecessarily become available as abiosimilar medicine. The cost ofdevelopment, production, and also thesize of the market (number of patients)have to be taken into account by apotential manufacturer. Industry mustbe able to develop and produce thebiosimilar medicine at a cost that allowsthem to market competitively at lower

prices than the reference product.

Figure 4: Stages of development of a biosimilar medicine

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Define and characterisethe reference product

Complete product &process development of thebiosimilar medicine

Confirm comparability of the biosimilar medicinewith the reference product

Physicochemical characterisationBiological characterisationPre-clinical testsPharmacokinetic (PK)/pharmacodynamic (PD)tests

PK/PD in men

All clinical trials for safety and effi cacy data

Non-Clinical

Clinical

}

}


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REGULATION OFBIOSIMILAR MEDICINES

Many of the questions around biosimilarmedicines were also raised about genericmedicines when they first became

widely available about 20 years ago. Theexperience gained in the development,regulation and use of generic medicines,together with extensive regulatoryand clinical experience with originatorbiopharmaceuticals, has led to theintroduction of new legislation andguidelines to regulate biosimilarmedicines.

The idea of a biosimilar medicine,with the concept of biosimilarity, wasintroduced into EU legislation in 2003and further developed with the adoptionof the EU pharmaceutical reviewand new legislation in 2004. Europe isleading in the development of a robustregulatory framework for biosimilarmedicines; it has been described asarguably one of the most complex issuesthat the European Commission has facedin the area of pharmaceuticals in the lastfive years.19

Scientific guidelines related to allmedicines have long been producedby the EMEA over many years, usually

after consultation with all the relevantstakeholders. These stakeholders includenational regulatory bodies, industry,clinicians, and patient groups.

In the past few years the EMEA, togetherwith the Committee for MedicinalProducts for Human Use (CHMP), the

Biotechnology Working Party (BWP)and the Working Party on SimilarBiological Medicinal Products (BMWP),and all the appropriate stakeholders,has developed a new series of specificguidelines dealing with all aspects of thedevelopment, production, testing andregulation of biosimilar medicines.

Quality, safety and effi cacy

In order for any medicine to bemarketed, it must be approved by

the relevant regulatory body.Allmanufacturers of medicinal productshave to demonstrate that the medicinesare:

of a specific and reproducible quality;

safe for patients to take (i.e.the risk of potential side effects

is considered acceptable whencompared to the benefits);

guaranteed to produce the desired clinically beneficial effect

(effi cacy).In order to obtain a marketingauthorisation, companies are requiredto supply data covering all these areas.These data are evaluated by the EMEAand its experts which will include stafffrom EU national agencies. If all thesedata are assessed as being satisfactorythen the medicine will be approved andwill receive a marketing authorisationfrom the European Commission whichwill allow the company to launch andmarket the medicine in Europe.

Pharmacovigilance

All European pharmaceutical companiesare legally required to monitor the useand effects of all their medicines. Theymust have systems in place to detect,assess, understand and communicate anyadverse reactions or any other medicine-related problem. This science andactivities of these processes are known asPharmacovigilance.

As part of pharmacovigilance, eachpharmaceutical company mustprovide a detailed description of theirpharmacovigilance system in themarketing authorisation application.

In addition, for every new medicine,including biosimilar medicines, a RiskManagement Plan (RMP)must besubmitted and agreed by the EMEA. TheRMP describes what is known about thesafety of the medicine and outlines howthe manufacturer will further monitorand fill any gaps in knowledge as wellas any measures needed to minimiseany risk from the medicine. This plan ispublished in the European AssessmentReport (EPAR) and needs to be updatedthroughout the lifetime of the medicine.

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Once the medicines are marketed,pharmaceutical companies must alsocontinuously evaluate the information

on the benefits and risks of theirmedicines. Therefore post-marketingsurveillance (PMS) activities areimportant. This involves:

Spontaneous reporting ofpossible adverse reactions fromthe medicine by the patient, or byhealth care professionals e.g. thepharmacist or clinician.

The preparation of regular reportsto review all available safety data.

These are known as Periodic

Safety Update Reports (PSURs). Post-Authorisation Safety Studies(PASS, sometimes called Phase IVstudies)

These studies are considered as a relevantpart of the Risk Management Plan.

The EMEA is also responsible for thedevelopment and maintenance ofthe EU pharmacovigilance database EudraVigilance that holds details ofall suspected serious adverse reactionsto medicines observed in the EU. All

pharmaceutical companies must nowsubmit information on serious adversereactions to the EMEA electronically.

On a larger scale, the EMEA and Headsof Medicines Agencies (HMA) from thenational regulatory authorities evaluatethe implementation of the European RiskManagement Strategy (ERMS) whichconcerns all medicines available in theEU.20Further improving the operation ofthe EU Pharmacovigilance System andstrengthening the science that underpins

the safety monitoring of medicines aretwo main areas covered by the ERMS.

Immunogenicity

Immunogenicity is the capabilityof a specific substance to inducethe production of antibodies inthe human body. It is importantto discuss immunogenicity in thecontext of biosimilar medicines.All biopharmaceuticals, in contrastto conventional pharmaceuticals,demonstrate a greater capacity to elicitsuch animmune reaction, because theyare polypeptides or proteins. In manypatients, such a response does not leadto any clinical consequences. However,the potential exists for general immune

reactions e.g. allergy, anaphylaxis. Inaddition, they may cause reactionswhich lead to a loss of effect fromthe medicine or rarely reactions whichcause an enhancement of activity. Thetype and level of immune response willbe examined during the developmentprocess, and after the product isauthorised and marketed as part of thepharmacovigilance activities, e.g. in thePSUR.

Immunogenicity may be influenced byfactors relating to the medicine itself e.g.

manufacturing process and formulation,and also by factors related to the patientand the disease and the treatment e.g.route of administration or depressedimmune response in cancer patients.21These factors are carefully evaluatedduring the development and assessmentof all biopharmaceuticals, includingbiosimilar medicines.

Substantial guidance for immunogenicityassessment is incorporated in the variousguidelines for biosimilar medicines today.

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Quality data

The quality dossier for biosimilar medicines meet the same standard as the reference product. Itincludes all the necessary data to establish quality for example:

Definitions and descriptions of the manufacturing process, and associated controltests and standards

Data on the consistency of manufacture (quality control of the process)

Data on analytical tests (molecular structure; potency and purity/impurity profile)

Pre-clinical data

Dossiers for biosimilar medicines include pre-clinical data.The amount of pre-clinical data required is specific to the product, and will be determined on acase-by-case basis.The data is generated through an abbreviated programme of in vitroand invivotests (which may include some animal testing).

Clinical data

Dossiers of biosimilar medicines also include clinical data, the results of trials in patients andhealthy volunteers. Due to the clinical experience accumulated over many years with the useof the reference product, the same extent of clinical testing needed for a new active substanceis not required. The design of the clinical trial programme takes into account the nature andthe characteristics of the medicine and its intended use; and how comparable the profile of thebiosimilar medicine is to that of the reference product. The closer the profiles of the medicines are,and the more the similarity has been demonstrated with appropriate comparative quality and pre-clinical tests, the more an abbreviated clinical trial programme can be accepted by the regulators.This means the very high development costs can be reduced. Abbreviated clinical trials also helpto ensure that unnecessary human testing does not take place. However, for most biosimilarmedicines, extensive trials have been or are required, often including several hundreds of patients.Companies applying for a marketing authorisation must submit all the results from their trials,

both positive and negative, which will be assessed on their own merits. A summary of thisinformation is available to the public through EPARs, produced by the EMEA and published ontheir website when the product is approved by the European Commission.

Pharmacovigilance

Biosimilar medicines, like all medicines, are carefully monitored in the clinical setting afterthe medicine has been made available. This will be achieved by pharmacovigilance and post-marketing surveillance (see next section). Information about how this will be achieved isincluded in the application in the description of the Pharmacovigilance Systems and also in theRisk Management Plan.

Table 2: Information required in dossiers submitted to the EMEA (called also marketing authorisation applications)


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ACCESS TO BIOSIMILARMEDICINES

Access to medicines

The World Health Organisation (WHO)states that access to medicines depends

on four factors.22

Rational selection and use ofmedicines

Affordable prices

Sustainable financing

Reliable health and supply systems

Most European countries have or aredeveloping strategies to address each ofthese factors.

Strategies to increase the affordabilityand availability of medicines to morepatients include promoting competitionand enhancing the availability of genericmedicines. Biosimilar medicines need tobe included in these strategies. Since aclear legal and regulatory environmenthas been established, a clear marketpathway for biosimilar medicines needsto be established in each individualMember State to enable access to thesemedicines as soon as possible after theirmarketing approval.

Indeed, the way countries determine

which medicines are selected and usedneeds to be adjusted to ensure biosimilarmedicines are made fully available.

Factors include marketing authorisationapproval, agreement on price andon how the biosimilar medicines arereimbursed and gaining the acceptanceof clinicians and patients in usingbiosimilar medicines as part of theirpractice and treatment. Access forpatients to biosimilar medicines is notautomatic; it requires proactive steps to

be taken by all relevant stakeholders.

Health economics

The use of medicines increases as peopleage, with those over 60 years using

on average three to four times moremedicines than when they were 30. It isestimated that the European populationaged over 60 will increase from under22% to more than 25% between 2000and 2015.23This equates to an additional50 million people in Europe agedover 60.

Current estimates for Europe show thatthe related expenditure on medicinesis growing at more than twice that ofthe growth of GDP (Gross Domestic

Product).23

Not surprisingly, the effectivemanagement of healthcare costs is keyfor all governments.

Biopharmaceuticals are some of theworlds most expensive medicines.On average, they cost much more perpatient as conventional pharmaceuticals.They cost many thousands of euros ormore per patient per year for the wholelife treatment of some rare metabolicdisorders. They are also often used totreat long-term conditions such asdiabetes, cancer, anaemia of chronickidney failure and multiple sclerosis,with a corresponding impact on clinicalpractice. As a consequence, payers musttry to fund the treatments consideredbest for the patient by their clinicians,while ensuring value for money and themanagement of finite resources.

These budgetary pressures can result inpatients not being treated in accordanceto national guidelines. For example, inFrance, around two-thirds of pre-dialysispatients would be expected to be on

erythropoietin (EPO), but figures showthat less than half receive the treatment.

The improved affordability of healthcarethat could result from the use ofbiosimilar medicines is real. It has been

estimated that 20% reduction in priceof five biopharmaceuticals off patent, orimminently off patent, would save theEU over 1.6 billion per year.24

The price differential between areference product and a biosimilarmedicine will depend on the relativedevelopment costs. Biosimilar medicinescan be expected to be offered at a pricebelow that of the reference product,partly as a result of production processeffi ciencies, and partly because ofthe reduced costs of a streamlined

development programme. The greatestsavings are likely to result from theclinical trial programme, since abiosimilar medicine, containing a knownand well-used substance, usually requiresless clinical data to support its approval.

The price differential and consequentialsavings are also likely to increase asbiosimilar medicines expand theirvolume share and it becomes standardpractice to use biosimilar medicinesamongst healthcare professionals and

patients.These additional savings differentialshould lead to significant and much-needed release of healthcare funds.

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Identification

As required by law for all medicines inthe EU, every biosimilar medicine willeither have an invented or brand name,or the name of the active substancetogether with the company name. Everybiosimilar medicine is consequentlyclearly identified by its unique name,which has to be formally accepted by the

EMEA prior to its approval.The first two biosimilar medicinesin Europe bear invented names(Omnitrope and Valtropin). Bothcontain the same active substance,somatropin. Somatropin is the scientificname for this active substance. Thescientific name is usually called theINN (International Non-proprietaryName)or generic name. The INN isalso approved by the EMEA during thescientific evaluation of the biosimilarmedicine.

The name of a medicine and the name ofits active substance are very importantfor the clear identification, safeprescription and dispensing as well as formonitoring the safety in use ofthe medicine.

Traceability

All pharmaceutical andbiopharmaceutical manufacturers use avariety of techniques to be able to tracetheir medicine at all times. This includes

unique labelling, batch numberingand packaging. Effective traceabilityalso covers systems which track theway medicines reach the patient viathe supply chain, and how medicinestaken by or administered to patients arerecorded and can be traced back in caseadverse reactions occur duringthe treatment.

Interchangeability

Interchangeability refers to the medical/pharmaceutical practice of switching onemedicine for another that is equivalent,in a given clinical setting. The regulatoryscientific data, published via the EPAR(European Public Assessment Report),should guide the decisions regardinginterchangeability.

If anoriginator companychanges itsmanufacturing process of their product,interchangeability between the pre andpost-change products is presumed solong as it is supported by comparabilitydata. For scientific consistency, the sameapproach should be taken for biosimilarmedicines.

It is important to reiterate that biosimilarmedicines match their referenceproduct in terms of quality, safety andeffi cacy. A demonstration of therapeutic

equivalence is required in order to adoptthe posology (dose recommendations) ofthe reference product.25

The extensive comparability andpost-marketing data will thereforedemonstrate that it is safe andeffi cacious to switch dose for dosefrom the reference product to thebiosimilar medicine.

Substitution

Substitution is a national administrativerule which requires or permits the switchfrom one medicine to another medicineproven to have the same quality, safetyand effi cacy. Substitution can takeplace at the retail pharmacy level, orat hospital pharmacies. It is governedby laws for generic medicines which

vary from country to country and takevarious scientific and non scientificparameters into account. As of August2007, this did not apply to originator andbiosimilar medicines.

A 2006 EGA internal survey26has shownthat while 71% of EU countries legallyallow generic substitution, in mostcases this can be opposed by both theclinician and the patient. Only 7% ofEU physicians are legally obliged toprescribe using the INN name only. Inthe UK, medical students are taught

to write prescriptions using INN butphysicians are not compelled by law todo so, and pharmacists are obliged todispense exactly what is written on theprescription. For 18% of EU countries,it is compulsory for pharmacists tosubstitute a generic medicine if one isavailable. Such an obligation is calledautomatic substitution.

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EVOLVING LANDSCAPE OFBIOSIMILAR MEDICINES

The period from 2007 to 2010 willsee more developments in relation tobiosimilar medicines, and healthcare

professionals and healthcare purchasersneed to ensure that they are awareof what is happening in this rapidlychanging environment.

A large number of patents of originatorreference products have lost theirprotection since 2001.

More biosimilar medicine applicationsare under assessment by the EMEA, witha number of additional applications inthe manufacturers pipeline. They mainlyconcern epoetins, interferons, insulins

and granulocyte-colony stimulatingfactors (G-CSFs).19

The EMEA guidelines not yet finalised bySeptember 2007 covered:

Therapeutic specific annex tothe overarching guideline - forrecombinant alpha-Interferons.27

Guideline for the immunogenicityassessment of biological /biotechnology-derived proteins21

(which applies to both originatorand biosimilar medicines).

Guidance note on comparabilityafter a change in themanufacturing process (whichapplies to both originator andbiosimilar medicines).28

Guideline on similar biologicalmedicinal products containing lowmolecular weight heparins.29

To keep ahead of the evolving landscape,further developments can be monitoredvia the EMEA web site.

In order to support all those interested inbiosimilar medicines, this handbook willbe followed by updates on theEGA website.

Table 3: Some examples of active substances of originator reference products

Scientific Name of the Active Substance Main Treatment Area

imiglucerase Gaucher disease

human insulin diabetes

interferon alpha 2ainterferon alpha 2b

various cancers, viralhepatitis B & C

interferon beta-1ainterferon beta-1b

multiple sclerosis

somatropingrowth hormonedeficiency

epoetin alfa

epoetin beta

anaemia associated with

chronic kidney failure

alteplase heart attack

filgrastim (granulocyte-colonystimulating factor, G-CSF)

neutropenia (in cancerpatients)

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FURTHER INFORMATION

More information on the issues summarised in this short guide can be foundat the following links:

Table 4: Useful website links

REVIEWERS

The material in this handbook was reviewed by an independent panel comprisingacademics, clinicians, lawyers, pharmacists, a patient advocacy group and a non-governmental organisation. The panel included:

Professor Colin Brown

Professor of Clinical Nephrology Renal Medicine and Transplantation, University ofSheffi eld, United Kingdom

Professor Theo Dingermann

Director, Institute of Pharmaceutical Biology, Goethe-University, Frankfurt, Germany

Professor Jzef Drzewoski

Department of Diabetology and Clinical Pharmacology Medical Universityof odz, Poland

Dr. Elisabeth Berthet

Doctor of Law and Doctor of Pharmacy, Lawyer at the Paris bar, Cabinet Armengaud &Guerlain, Paris, France

Dr. Mary Smillie

Bird & Bird, London, United Kingdom

European Medicines Agency (EMEA) http://www.emea.eu.int/

European Commission, Enterpriseand Industry

http://ec.europa.eu/enterprise/pharmaceuticals/index_en.htm

World Health Organisation (WHO) http://www.who.int/en

European Generics medicinesAssociation (EGA)

http://www.egagenerics.com/

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CONTRIBUTORS

Dr. Tim Oldham

President, Asia Pacific, Hospira, Australia

Suzette Kox

Senior Director Scientific Affairs EGA, Brussels, Belgium

This handbook was commissioned and funded by the following members of theEuropean Generic medicines Association (EGA):

Apotex Inc.

BioGenerix AG

Hospira Inc.

Sandoz International GmbH

STADA Arzneimittel AG

Teva Pharmaceuticals Europe B.V.

The report has been written by an independent Healthcare Consultant together

with the following Editorial Board: Dr. Bruce Clark, Dr. Sandy Eisen, Lotte Huinink,Dr. Ajaz Hussain, Dr. Erich Kohler, Marcy Macdonald, Dr. Dieter Moecke, and IngridSchwarzenberger.

Disclaimer:

The information in this handbook contains the views of the EGA, and not the viewsof the EMEA or any national regulatory agency.

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GLOSSARY

Active substance:Active ingredient or molecule whichgoes into a specific medicine and whichprovides this medicine with propertiesfor treating or preventing one or severalspecific disease(s)

Anaemia:Low red blood cell count

Anaphylaxis:Acute and severe allergic reactionin humans

Antibodies:Large proteins used by the immunesystem to identify and neutralise foreignobjects e.g. bacteria, viruses

Adverse reaction:

Any unexpected or expected reactionfollowing the administration of a givenmedicine that is harmful to the patient

Biopharmaceuticals:Medicines made by or derived from livingorganisms using biotechnology

Biotechnology:Technology which manipulates livingorganisms so that they reproduce humanhormones e.g. insulin

Bioequivalence study:Assessment of the comparativebehaviour in the body of two medicines

Bioequivalent:Two medicines are consideredbioequivalent if they are shown tobehave in the body in the same way

Biosimilarity:Capacity of a medicine to show similarityin terms of quality, safety and effi cacy toa reference biological medicine to whichit has been compared

Biosimilar medicine:Medicine which is approved by theregulatory authorities to be similar interms of quality, safety and effi cacy toa reference biological medicine with towhich it has been compared

Comparability:The scientific evaluation of a comparisonof two medicinal products to determineequivalence and any detectabledifferences at the level of quality, safetyand effi cacy

Formulation:The recipe and presentation of amedicine

Gaucher disease:Rare inherited disorder; people with this

disease do not have enough of a specificenzyme called glucocerebrosidase

Generic medicine:Medicine which has the samecomposition in active substance (s)and the same pharmaceutical formas the originator reference medicine,and whose bioequivalence with theoriginator reference medicine (i.e.the same behaviour in the body) hasbeen demonstrated by appropriatebioavailability studies

Glycosylation:The type and length of any sugar orcarbohydrate groups attached to a givenmolecule

EudraVigilance:Data processing network andmanagement system for reporting andevaluating suspected adverse reactionsduring the development and followingthe marketing authorisation of medicinalproducts in the European Economic Area(EEA)

EU Pharmaceutical Review:European legislative process whichadopted a new EU pharmaceuticallegislation on 31 March 2004

INN(Internationally Non-proprietary

Name):Scientific or generic name of anactive substance. INNs for new activesubstances are allocated by the WorldHealth Organisation (WHO) in Geneva.The INN is a unique and universallyaccessible name. For generic andbiosimilar medicines cross-referring toreference products, it is the regulatoryauthority who decides whether the INNof the active substance as submitted forthe generic or the biosimilar medicine isscientifically acceptable

Immune response/reaction:Production of antibodies by the humanbody in reaction e.g. to viruses andsubstances recognized as foreign andpossibly harmful

Immunogenicity:Capability of a specific substance toinduce the production of antibodies inthe human body which is also called animmune response/reaction.

Interchangeability:

Refers to the medical/pharmaceuticalpractice of switching one medicine foranother that is equivalent, in a givenclinical setting

In vitro:

Biological or chemical work done in thetest tube (in vitrois Latin for in glass)rather than in living systems

In vivo:

Experiments or tests carried out in livingorganisms (as opposed to the laboratory)

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Heads of Medicines Agencies:Grouping of Heads of Member StatesCompetent Authorities who deal withthe System of Medicines Regulation, andwho provides a forum for the exchangeof views on issues of Community interest

Molecule:Compound made by atoms in a definitearrangement held together by strongchemical bonds

Originator Company:Company first to develop and produce aspecific medicine (biopharmaceutical orpharmaceutical)

Patent:Set of exclusive rights granted to acompany for a set period of time

in exchange for the disclosure ofits invention

Phase I study or trial:Study determining that a medicine issafe in healthy humans and helpingto predict the dosage range for themedicine. These are often conducted inhealthy volunteers

Phase III study or trial:Study involving a larger group ofpatients which helps to determine if themedicine can be considered both safeand effective in a real clinical setting

Pharmaceuticals:Conventional or traditional chemicalmedicines

Pharmacodynamic tests:Study of the action/effects of a medicineover a period of time

Pharmacokinetic tests or studies:To determine how medicines areabsorbed, distributed, metabolised andeliminated by the body

Pharmacovigilance:Defined by the World HealthOrganization as the science and activitiesrelating to detection, assessment,understanding and prevention of anyadverse effects or any other medicine-related problem

Physicochemical characterisation:Test to determine the properties ofa molecule or active substance e.g.molecular size/weight, chemicalstructure, purity

Polypeptides:Molecules made up of chains of aminoacids, which may have activity in thehuman body. They contain less aminoacids, and hence have lower molecular

weights than proteinsPost-Authorisation Safety Study:Clinical trial carried out in accordancewith the terms of a marketingauthorisation and conducted with theaim of identifying or quantifying asafety hazard relating to an authorisedmedicinal product

Pre-approval inspection:Any inspection (e.g. of themanufacturing plant) performed by aregulatory authority before the medicine

receives its marketing authorisationProteins:Large molecules made of amino acidsarranged in a chain. E.g. erythropoietin isa protein

Reference (originator) product:Medicine, which has been developedand produced by an originator company,and which has been approved by thenational regulatory authorities or theEuropean Commission on the basis of afull registration dossier

Risk Management Plan:Plan which describes what is knownabout the safety of the medicine andoutlines how the manufacturer willfurther monitor and fill any gaps inknowledge as well as any measuresneeded to minimise any risk from themedicine

Scientific peer review:Scientific review and validation of

documents or data performed by peers,who are independent scientists withsuitable qualifications and experience

Substitution:Refers to a national administrative rulewhich requires or permits the switchfrom one medicine to another medicineproven to have the same quality, safetyand effi cacy. Substitution can take placeat retail pharmacy level, or at hospitalpharmacies. It is governed by laws forgeneric medicines which vary fromcountry to country and take various

scientific and non scientific parametersinto account

Traceability:Refers to the ability to trace every batchof a medicine in the distribution andsupply chain as well as to trace backwhich medicine has been taken by oradministered to a patient

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REFERENCES

1IMS MIDAS, Therapy Forecaster, Market

Insights, Sep. 2006

2Scrip-World Pharmaceutical News-17

September 2007 (Ref. S00970766)

3OECD Health Data 2006, OECD, Paris

June 2006 (OECD in figures 2006-2007)

- ISBN 9264022635

4European Public Assessment Report:

Valtropin (Doc. Ref.: EMEA/H/C/602,

approved on 24 April 2006)

5European Public Assessment Report:

Omnitrope (Doc. Ref.: EMEA/H/C/607,

approved on 12 April 2006)

6Directive 2004/27/EC of the European

Parliament and Council of 31 March

2004 amending Directive 2001/83/EC

on the Community Code relating

to Medicinal Products for Human

Use; and Regulation (EC) 726/2004

of the European Parliament and of

the Council of 31 March 2004 laying

down Community procedures for

the authorisation and supervision of

medicinal products for human and

veterinary use and establishing a

European Medicines Agency

22

7EMEA Annual Report 2006 (Doc. Ref.:

EMEA/MB/24167/2007/EN/Final), page

23/134

8

Guideline on Similar BiologicalMedicinal Products (Doc. Ref.: EMEA/

CHMP/437/04, London, 30 October 2005)

9Guideline on Similar Biological

Medicinal Products containing

Biotechnology-derived Proteins as Active

Substance: Quality Issues (Doc. Ref.:

EMEA/CHMP/BWP/49348/2005, London,

22 February 2006)

10Guideline on Similar Biological

Medicinal Products containingBiotechnology-derived Proteins as

Active Substance: Non-clinical and

Clinical Issues. (Doc. Ref.: EMEA/CHMP/

BMWP/42832/2005, London, 22 February

2006)

11Annex to Guideline on Similar

Biological Medicinal Products containing


Substance: Non-clinical and Clinical

Issues - Guidance on Similar MedicinalProducts Containing Recombinant

Granulocyte-Colony Stimulating

Factor (Doc. Ref.: EMEA/CHMP/

BMWP/31329/2005, London, 22 February

2006)





Issues - Guidance on Similar MedicinalProducts Containing Recombinant

Human Soluble Insulin (Doc. Ref.: EMEA/

CHMP/BMWP/32775/2005, London, 22

February 2006)





Issues - Guidance on Similar Medicinal

Products Containing Somatropin (Doc.

Ref.: EMEA/CHMP/BMWP/94528/2005,

London, 22 February 2006).





Issues - Guidance on Similar Medicinal

Products Containing Recombinant

Erythropoietins (Doc. Ref.: EMEA/CHMP/

BMWP/94526/2005 Corr., London, 22

March 2006).


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15The community register of medicinal

products, European Commission,

Enterprise and Industry

16

Work Programme for the EuropeanMedicines Agency 2007, adopted by the

Management Board on 19 December

2006 (Doc. Ref.: EMEA/MB/428793/2006/

EN/Final)

17 Doc. Ref.: EMEA/74562/2006

18EMEA Press Release of 18 October

2007 (Doc. Ref. EMEA/479200/2007)

19Personal testimony of Nicolas

Rossignol (European Commission) atthe Hearing before the Senate Help

Committee on Follow-On-Biologics

(March 2007) (Introduction, page 1)

20Public Status Report on the

Implementation of the ERM Strategy

/Reporting Period Mid 2005-Mid

2007)(Doc. Ref.: EMEA/168954/2007)

21Draft Guideline on Immunogenicity

Assessment of Biotechnology-derived

Therapeutic Proteins (Doc. Ref.: EMEA/

CHMP/BMWP/14327/06, London 24

January 2007)

22World Health Organization website

(Globalization, trade and health/Access

to medicines)

23UN Population division, OECD 2001

24 Oldham, T.Strategies for entering

the biosimilar market, in: Biosimilars

Evolution or Revolution? (November2006). Biopharm Knowledge Publishing,

London

25 Report of WHO Informal Consultation

on Regulatory Evaluation of Therapeutic

Biological Medicinal Products (19 - 20

April, 2007). The report contains the

collective views of an international

group of experts, and does not

necessarily represent the decisions or

the stated policy of the World Health

Organization

262006 (Internal) MARKET REVIEW:

The European Generic Pharmaceutical

Markets. EGA, Brussels

27Annex to the Guideline on Similar


Biotechnology-derived Proteins as

Active Substance: (Non) Clinical Issues

- Concept paper on similar biological

medicinal products containingrecombinant alpha-interferon (Doc.Ref.:

CHMP/BMWP/7241/2006, London, 26th

April 2006)

28Draft Guideline on Comparability

of Biotechnology-derived Medicinal

Products after a Change in the

Manufacturing Process Non-clinical

and clinical issues (Doc. Ref.: CHMP/BMWP/101695/2006, London 24 January

2007)

29A concept paper on similar biological

medicinal products containing low

molecular weight heparins (non)

Clinical Issues (Doc. Ref.:EMEA/CHMP/

BMWP/496286/2006).

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ACRONYMS AND ABBREVIATIONS

BMWP Working Party on Similar Biological Medicinal Products (EMEA)

BWP Biotechnology Working Party (EMEA)

CHMP Committee for Medicinal Products for Human use (EMEA)

EC European Commission

EEA European Economic Area

EGA European Generic medicines Association

EMEA European Medicines Agency

EPAR European Public Assessment Report

ERMS European Risk Management Strategy

EPO Erythropoietin

EU European Union

G-CSF Granulocyte-Colony Stimulating Factor

GDP Gross Domestic Product

GMP Good Manufacturing Practice

HMA Heads of Agencies

INN International Non-proprietary Name

MAB Monoclonal Antibody

NCA National Competent Authority

PAI Pre-Approval Inspections

PD Pharmacodynamics

PK Pharmacokinetics

PASS Post-Authorisation Safety Studies

PMS Post-Marketing Surveillance

PSUR Periodic Safety Update Reports

RMP Risk Management Plan

WHO World Health Organisation

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EGA | EUROPEAN GENERIC MEDICINES ASSOCIATION

Formed in 1993, the EGA is the offi cial representative bodyof the European generic pharmaceutical industry, which is atthe forefront of providing highquality affordable medicinesto millions of Europeans and stimulating competitiveness andinnovation in the pharmaceutical sector.

The EGA and its members work with European nationalgovernments and the EU institutions to develop affordablesolutions for pharmaceutical care and to increase Europescompetitive strength in the global pharmaceutical market

LEGA, cre en 1993, est le reprsentant offi ciel de lindustriepharmaceutique gnrique europenne, au premier rang dela production de mdicaments de haute qualit et abordablespour des millions deuropens stimulant ainsi la concurrence etlinnovation dans le secteur pharmaceutique.

LEGA ainsi que ses membres, oeuvrent avec les gouvernementsnationaux europens et les institutions europennes audveloppement de solutions conomiques pour la sant et aurenforcement de la concurrence europenne sur le marchpharmaceutique au niveau mondial

EUROPEAN GENERIC MEDICINES ASSOCIATIONRue dArlon 50 B-1000 Brussels Belgium

T: +32 (0) 2 736 84 11 F: +32 (0) 2 736 74 38

Documents

EGA Handbook on Biosimilar Medicines