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A Focus onBiosimilarMedicines

Biological Medicines

EXECUTIVE SUMMARY

A Focus onBiosimilarMedicines

Biological Medicines

Biotechnology has enabled the discovery of treatments for a variety of serious diseases.

Worldwide, over 350 million patients have benefited from approvedmedicines manufactured through biotechnology. Currently, over 650new biological medicines and vaccines are be developed to treat more than 100 diseases. As the exclusive rights for these biologicalmedicines expire, similar biological medicines, or “biosimilars”, arebeing developed, with some already available on European markets.

Biological medicines are comprised of proteins and other substances that are often naturally produced in the human body. In healthcare,biotechnology is being used inthree primary areas: therapeuticmedicines, vaccines and diagnostics. When compared tochemical medicines, biologicalmedicines are generally morecomplex and usually much largerin size than chemical medicines.The complexity is predominantlydue to the manufacturing process for biological medicine,as they are developed in livingsystem the exact characteristicsand properties are highlydependent on the manufacturingprocess. Chemical medicinescan be approved either bynational medicines authorities orby the ‘centralised procedure’carried out by the EuropeanMedicines Agency (EMA), however all biological medicinesproducts must follow the ‘centralised procedure’ for approval.

Due to the composition andlarge molecule size of biologicalmedicines, they have the inherentpotential to induce (unwanted)

immune reactions. Therefore, in order to identify unwantedimmune reactions, and for post regulatory approval commitments, treating physicians should state thebrand name and batch number, as opposed to theInternational Non-ProprietaryName (INN) when prescribing.Furthermore, due to the uniquenature of biosimilars, thereshould not be automaticsubstitution of the referenceproduct, this decision should be left with the treatingphysician.

Generics and Biosimilars havean important role to play in fostering competition in themarket place, and therebycontributing to the sustainabilityof healthcare budgets. However,as the research and developmentcosts of biosimilars are muchhigher than generics, suitablepricing and reimbursement environments are needed to foster the development of new products. Furthermore,adequate intellectual propertyprotection is vital to ensure that companies are able to fundresearch and development

of biological medicines, andtherefore develop and producemore potential treatments.Upon expiry of such protection,biosimilar products (unlike chemical generics these are not exact copies, as they aremade in living systems the exactcharacteristics are dependentupon the manufacturing process)can enter the market to competewith the original “reference product”.

So far the European Union hasapproved 7 biosimilars, across 3 product classes. In the UnitedStates, the Biologics PriceCompetition and InnovationAct, signed into law in March2010, created a statutory framework for the approval of biosimilars by the Food andDrug Administration (FDA).Over the last two years, the biosimilar market shares havesteadily increased in most countries. In several Europeancountries, biosimilars now havea higher volume market sharethan the reference product, and this trend appears to beaccelerating.

02 INTRODUCTION

03 HEALTHCARE BIOTECHNOLOGY: INTRODUCTION TO THE SCIENCE

03 What are biological medicines and how do they work?03 How do biological medicines differ from chemical medicines?

Key differentiating factors.03 How are biological medicines manufactured?05 Intellectual property for biotech medicines

06 BIOLOGICAL MEDICINES – CURRENT ISSUES

06 Naming, Pharmacovigilance and Risk Management Plans07 Interchangeability07 Substitution08 Impact on healthcare budget and pricing08 The regulation of biologicals in Europe, including biosimilars

09 THE MARKET FOR BIOSIMILARS

09 Which biosimilars are currently available in Europe?09 What about the rest of the world?09 What does the entry of biosimilars in the market mean to originator products?

10 THE POTENTIAL IMPACT OF BIOSIMILARS

10 For patients10 For healthcare professionals10 For payers

11 GLOSSARY OF KEY TERMS

12 REFERENCES

TABLE OF CONTENTS INTRODUCTION

01

Biological Medicines A Focus on Biosimilar Medicines

Biotechnology has enabled the discoveryof treatments for a variety of seriousdiseases. Worldwide, more than 350 million patients have already benefitedfrom approved medicines manufacturedthrough biotechnology.

These medicines help treat or prevent many rare and severe diseases including cancers, heart attacks,stroke, multiple sclerosis, diabetes, rheumatoidarthritis and autoimmune diseases. In addition, over 650 new biological medicines and vaccines are currently being developed to treat more than 100 diseases 1.

As the exclusive rights (patents and other data protection) for certain biological medicines expire,similar biological medicines, or "biosimilars", arebeing developed. Several biosimilars are alreadyavailable on European markets. This document is intended to explain the complexities and specificities of biological medicines, including biosimilar medicines.

02

Biological medicines arecomprised of proteins andother substances that areoften naturally produced in the human body.

1. "Engaging with the global monoclonal antibodyand biologicals markets" Jean-Claude Muller;Special Advisor, Innovation and InternationalRelationships; Formerly Senior Vice President,R&D Prospective and Strategic Initiatives; Sanofi-Aventis

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03

Biological Medicines A Focus on Biosimilar Medicines

04

What are biological medicines and how do they work?

Biological medicines are comprised of proteins (such as growth hormone, insulin, erythropoietin, enzymes, and antibodies) and other substances that are often naturally produced in the humanbody. Biotechnology uses thegreat potential in living systems(plant or animal cells, bacteria,viruses and yeasts) and moderntechnologies to produce biolo-gical medicines to treat diseasesand genetic disorders in humans.

Biotechnology in healthcare iscurrently being used in three

primary areas: therapeutic medicines (also including advanced therapies such as celland gene therapy), vaccines and diagnostics. In this brochure,we use the term “biologicalmedicine” or “biotech medicine”as a synonym for therapeuticproteins and monoclonal antibodies.

How are biological medicines manufactured?

Manufacturing biological medicines is more complex than the production of chemicalpharmaceuticals. There are anumber of reasons for this, including the nature of the starting material and

the very high level of precision required.

Most biological medicines are made using a genetically-modified cell construct or cellline. Each biotech company has its own master cell bank producing unique cell lines replicated for manufacturing and develops its own proprietary(unique) manufacturing processes.

The production of biologicalmedicines involves processessuch as fermentation and purification. Even very minorvariations to these manufacturingprocesses, for example in temperature, can result in

significant changes in the physical and clinical propertiesof the biological medicine produced. It is therefore vital to control precisely the manufacturing processes and the environment inside aproduction facility, to obtainconsistent results and to guarantee the safety and efficacy of the end product.Production also requires a highlevel of monitoring and qualitytesting: typically around 250 in-process tests are conductedfor a biological medicine, compared to around 50 tests fora traditional chemical medicine.

Biological medicines may have higher variability. As biological medicines are produced by living systems, such as cell lines, theymay show a higher variability in their structure and characteristics than traditionalpharmaceuticals produced by chemical synthesis, unless processes are carefullycontrolled. This variability is highly dependent on the master cell line selectedand used by each manufacturer, as well as materials and manufacturing conditionsused throughout the production process.

Biological medicines are more complex. Because biological medicines are generally far more complex than chemicalpharmaceuticals, modifications to their manufacturing process need to be evaluated carefully, to ensure the drug's efficacy and tolerability are not compromised. Furthermore, the complexity of biological medicines makes theiranalytical characterisation more challenging than that of small molecules (chemically synthesised). Small changes in the manufacturing processes of biological medicines can lead to major changes in the products, as these changescould alter their tri-dimensional structure and their safety and efficacy profile.

Biological medicines have the potential to provoke immune reactions. Biological medicines have the potential to be recognised by the body as‘foreign’ and therefore have the inherent potential to induce (unwanted)immune reactions, due to their composition and large molecular size. Chemicalmedicines, on the other hand, are usually too small to be recognised by theimmune system and are of a different composition.

The potential to induce an immune reaction in the body (immunogenicity) is adouble-edged sword for biological medicines. Vaccines specifically exploit theirimmunogenic potential by provoking an immune response that recognises and"fights off" an "invader" substance. However, for some medicines based on

How do biological medicines differ from chemical medicines? Key differentiating factors. proteins, stimulating an immune response is regarded as undesirable (with the

notable exception of vaccines where this immune response is the expected effect).

Most of the immune responses that occur are mild and do not have negativeeffects on the patient. However in rare cases, unwanted immune reactions canlead to severe and detrimental effects on the health of a patient. One example isthe appearance of so-called "neutralising" antibodies that can make the therapeuticprotein in the medicine ineffective. Neutralising antibodies can be of particularconcern for biological medicines that resemble the patient's own proteins (toreplace insufficient substance levels in the patient), as they can trigger the bodyto fight off the protein injected in the medicinal product and, in rare cases, anyremaining protein produced by the patient's own body. This immunogenic reactioncan take years to develop and can happen at any time during treatment (aftershort-, medium and long-term use). This reaction can persist for years after thebiological medicine has stopped being administered to the patient. Therefore,immunogenicity assessment through clinical studies plays a major role in thedevelopment of biological medicines.

Biological medicines are typically administered via injections or infusions.A molecule of a biological medicine is typically a protein made of one or severalchains of several hundred amino acids within a complex three-dimensionalstructure. Because proteins are digested when taken orally, typically biologicalmedicines must be administered by injection. Medicines based on small molecules(traditional pharmaceuticals) usually come in tablet or capsule form.

Biological medicines usually need special transport and storage conditions. Biological material generally degrades quickly when handled inappropriately, particularly if they are subject to high temperature. Therefore, biological medicinesusually need to be stored in a refrigerator and should only be handled underspecific conditions.

the complexity ofbiological medicinesmakes their analyticalcharacterisation morechallenging than thatof small molecules.

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HEALTHCARE BIOTECHNOLOGY: INTRODUCTION TO THE SCIENCE

Biological medicines are generally more complex andusually much larger in size thanchemical medicines, which areproduced by chemical synthesis.As biological medicines are madein living systems, their exactcharacteristics and propertiesare highly dependent on themanufacturing process.Therefore, manufacturing andprecise characterisation tends to be more difficult when compared to chemical medicines,the ingredients of which aremore easily identifiable and can be exactly reproduced.

BIOLOGICAL MEDICINES – CURRENT ISSUES

05

Biological Medicines A Focus on Biosimilar Medicines

06

Intellectual property forbiotech medicines

Innovative medicines benefitfrom a certain period ofintellectual property protection,via patents and other exclusiverights, such as data protection.Patent rights give the patentholder (often, but not always,the manufacturer) the right to prevent others from manufacturing, selling, using and importing the productduring a limited period of time.A patent also grants the right to prevent others from using aspecific process, or selling a product made by that process,during a limited period of time.

Patents benefit both companiesand society at large, as theyenable important scientific information to be made publiclyavailable, which might otherwiseremain hidden. Patents also makeinvestments in biotechnology

R&D more attractive, which inturn leads to more innovation,and therefore more potentialtreatments.

Data exclusivity grants a period of time after MarketingAuthorisation, during whichcompetitors are not allowed toenter the market with a follow-on product (i.e. generic or bio-similar). The “follow-on” productgenerally uses an abbreviatedregulatory approval procedure.

Intellectual property protectionis vital for companies that develop and manufacture newmedicines, as it enables them to recoup their investments andfurther invest in the research anddevelopment of new medicines.As such, the provision of an adequate intellectual propertyprotection system is critical toensure a steady stream of newmedical advances, to greatpublic benefit.

Small molecule medicines, produced by chemical synthesis,can generally be replicated fairlyeasily by unrelated manufacturersafter the expiry of intellectualproperty protection. Such copiesof the original chemical medicinesare called "generics". In contrast,biological medicines made byunrelated manufacturers after theexpiry of intellectual propertyprotection are not exact copies ofthe original biological medicinesbecause they are made in living systems and their exactcharacteristics and propertiesare highly dependent on themanufacturing process. Thesenew versions of biological medicines are called "similarbiological medicinal products"or "biosimilars". In both cases,the originator product is calledthe "reference product".

The specific characteristics of biologicals are taken into account by the European legislator and regulator:

1. The updated European legislation on pharmacovigilance, due to be implementedmid-2012, establishes that Member States must make sure that “all appropriatemeasures are taken to identify when biological medicinal products are prescribed,dispensed, or sold in their territory which is the subject of a suspected adversereaction report, with due regard to the name of medicinal product (…) and thebatch number.”

2. All biological medicines, originator and biosimilar products, need to have a"Risk Management Plan" in place. This Risk Management Plan defines a set of"pharmacovigilance activities and interventions designed to identify, characterise,prevent or minimise risks relating to medicinal products, and the assessment of the effectiveness of these interventions". Assessment of the immunogenicity is a key measure in the Risk Management Plan of any biological medicine.

Biological medicinesmade by unrelatedmanufacturers after the expiry of intellectualproperty protection arenot exact copies of the original biologicalmedicines.

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Naming,Pharmacovigilanceand Risk Management Plans

Each active ingredient in a medicine has an InternationalNon-proprietary Name (INN –for example “acetylsalicylic acid” is the INN of the activeingredient in “aspirin”) as well as a brand name.

In the case of biological, INN canbe either identical or differentfor similar products made by different manufacturers. For instance, the INN forrecombinant growth hormone, is the same (somatropin) for allgrowth hormones made by different originators or biosimilarcompanies. By contrast, the INN for recombinant human erythropoietin is different for different originator products(epoetin alpha, beta or theta)and can be identical or differentfor biosimilar products (epoetinalpha or zeta).

European Medicine Agency(EMA) guidance indicates standard reporting of brandname, manufacturer’s name andbatch number for all adverseevents caused by biologicalmedicines. Therefore, biologicalmedicines should only be prescribed by their brand name,

and not by their INN, whichidentifies medicines bytheir active pharmaceuticalingredients. Despite the factthat it may be possible for activeingredients in different biologicalmedicines to share the sameINN, patients may experiencedifferent immunogenic reactionswith different products.Additionally, not all biologicalmedicinal products have thesame indications, administrationschedules, administration systems or side effect profiles.

The need for correct and preciseidentification is strengthened by the need to have robustpharmacovigilance carried outafter marketing authorisation.Due to the variability ofbiologicals, the correct productidentification in case of adverseevents is important.

Biosimilars may be approved by regulatory authorities on the basis of demonstrated comparability to the referenceproduct, a limited clinical database and often data on themain indication only. Holders of marketing authorisations forbiological medicines, referenceproducts as well as biosimilars,may have post-approval commitments defined in risk

management plans, to characterise safety profiles morefully, to establish long-term safety.

As already discussed, biologicalshave the inherent potential toinduce (unwanted) immune reactions. Immune reactions maytake years to develop, thereforebiologicals are usually treateddifferently to chemical medicinesby regulatory authorities. Whilstmuch is now known about thefeatures of biological medicinalproducts that cause immunereactions (for example highcontent of host cell proteins andcertain routes of administration),it is not currently possible toaccurately predict immunogeni-city in humans. Immunogenicityis however assessed through non-clinical assessment in animals,and in humans within the scopeof clinical trials and thoroughpost-marketing surveillance.

At the time of approval (for both originator and biosimilarbiologicals), information on thesafety of the medicinal productis relatively limited for severalreasons, including a limitednumber of patients in clinicaltrials, limited time of exposureto the medication and, usually, a rather strictly defined patientpopulation.

Biological Medicines A Focus on Biosimilar Medicines

Interchangeability

Interchangeability of medicinalproducts refers to the situationwhere one product can be interchanged for another equivalent product in a clinicalsetting, without the risk of anegative health outcome.

In order to gain a marketingauthorisation in Europe, biosimilarapplicants need to demonstratesimilarity to the reference product. Assessments of interchangeability and substitutability are not part of the scientific evaluation bythe European Medicines Agency(EMA) and therefore, no conclusion on interchangeabilityor automatic substitution can bemade based on the grant of amarket authorisation. Decisionson automatic substitution liewithin the responsibility of theMember States. Unless productsare designated as substitutable(see below), the decision as towhich product should be usedand whether treatment shouldor could be changed to anotherproduct lies with the treatingphysician.

Substitution

Automatic substitution (or generic substitution) is when apharmacist substitutes a genericmedicine for the brand nameversion of the same active ingredient, with no obligationto inform the treating physician.Some countries make genericsubstitution mandatory undercertain conditions, for examplewhere the doctor prescribes by INN.

Generic substitution is often linked to reimbursement, assome health insurance schemeswill only reimburse the patientfor the cost of the generic version of a product. The result

of this can be that a patient whorefuses the generic version andinsists on the original productmay be liable to pay the diffe-rence in cost. Generic versionsof chemical pharmaceuticals that have demonstrated theirbioequivalence may generally be substituted with no risk to patient safety.

However, the EMA has specifically stated that "sincebiosimilars and biological reference products are not identical, the decision to treat apatient with a reference productor biosimilar medicine should betaken following the opinion of aqualified health professional".The physician’s involvement isparticularly relevant, as not all biological medicines willnecessarily have the same indications, administration schedules, administration devices or side effect profiles.

Furthermore, if automatic substitution were to take place,it could confound pharmaco-vigilance when adverse reactionsoccur, especially immune reac-tions, as it is more difficult toevaluate which product is responsible for the reaction ifthe product has been repeatedlyswitched during treatment.

A number of countries haveeither established legislativemeasures to prohibit the automatic substitution of biological medicines or havegiven regulatory advice on theuse of biologics (including prescription by brand names).

Based on the above, countriesthat currently allow automaticsubstitution of biologicals shouldtake the necessary measures tostop this practice in the absenceof data that demonstrate inter-changeability. Therefore, anychange of treatment with a

biological medicine should currently only be made underclose medical supervision by the physician, with the patient’sconsent.

Impact on HealthcareBudget and Pricing

Generics and biosimilars have animportant role to play to fostercompetition in the marketplace,contributing thereby to the sus-tainability of healthcare budgets.

Price reductions for biosimilarsare generally not as those forgeneric medicines for a numberof reasons. Firstly, biologicalmedicines, including biosimilars,are generally more complex andcostly to produce and develop.Secondly, the regulatory approvalrequirements and post-marketingsurveillance for biosimilars aremore rigorous than for genericmedicines, thus adding a furtherlayer of cost to developing abiosimilar (e.g. unlike generics,biosimilars usually require independent non-clinical and clinical trials to be undertaken).

Therefore, R&D costs requiredfor the approval of a biosimilar -ranging on average from USD75 to USD 250 (approximately

€50 to €170 million)2 - are muchhigher than those for a generic.The exact price level of a biosimilar will depend on a number of factors, namely thepricing and reimbursement environment of each country,competitiveness of the marketand the desire to encourage the future development of new products.

Currently the number of biosimilars is low partly becauseonly a few biological medicineshave lost their market exclusivity.Potential savings, due to theirlower list prices, are thereforelimited as the products competein market segments that onlyrepresent a small portion of totalhealthcare expenditure.

The regulation of biological in Europe, including biosimilars

Depending on the disease category, chemical medicinescan be approved either by thenational medicines authorities

of the individual EU MemberStates or by the "centralisedprocedure" for approval carriedout by the European MedicinesAgency (EMA). In contrast, all new biological medicinal products, including biosimilars,have to follow the centralisedprocedure.

Applications submitted to theEMA are assessed by itsCommittee for Human MedicinalProducts (CHMP), which can givea positive or negative opinion.Upon receipt of a positive opinion from the EMA, theEuropean Commission issues amarketing authorisation, which isvalid for all EU Member States.

Since 2003, the European Union has created a legal andregulatory pathway to enablethe development and marketingof biosimilar medicines.Directives 2003/63/EC and2004/27/EC created the legislative route and the EMAhas subsequently developed anumber of regulatory guidelines

concerning the data required forthe approval of a biosimilar.

Besides the "overarching" general guidelines on biosimilars,the EMA has also developedguidelines on quality, non-clinicaland clinical issues, as well asproduct-specific guidelinesannexes (for example insulin,epoetin, somatropin, granulocyte-stimulating growth factor, interferon-alfa and low-molecularweight heparin). At the time ofpublication of this document,further guidelines are being prepared, including guidelineson follicle stimulation hormone,interferon-beta and monoclonalantibodies.

The EMA's "overarching" guidelines on biosimilars specifically state that biosimilarproducts are "by definition" not generics, and that the generic approach to approval"is scientifically not appropriate"for biosimilars.

The EMA defines biosimilars in "Questions and Answers on biosimilar medicines" as:

"A biosimilar medicine is a medicine which is similar to a biological medicine that hasalready been authorised (the 'biological reference medicine'). The active substance ofa biosimilar medicine is similar to the one of the biological reference medicine.Biosimilar and biological reference medicines are used in general at the same dose totreat the same disease. Since biosimilar and biological reference medicines are similarbut not identical, the decision to treat a patient with a reference or a biosimilarmedicine should be taken following the opinion of a qualified healthcare professional.The name, appearance and packaging of a biosimilar medicine differ to those of thebiological reference medicine."

Furthermore, the EMA Questions and Answers document states that the "legislation definesthe studies that need to be carried out to show that the biosimilar medicine is similar andas safe and effective as the biological reference medicine". To this end, the biosimilarapproval pathway requires the manufacturer to demonstrate similarity with the referenceproduct for quality, safety and efficacy. Specifically, the biosimilar must demonstrate that ithas no significant clinical differences to the reference product. Biosimilar manufacturers mustprovide all of the non-clinical, pre-clinical and clinical data required to demonstrate thesimilarity of their product to the reference product, without the need to repeat unnecessarytests and trials.

07 08

2. Industry average source: Sandoz internalestimates. Conversion in € done in July 2011

THE MARKET FOR BIOSIMILARS THE POTENTIAL IMPACT OF BIOSIMILARS

Biological Medicines A Focus on Biosimilar Medicines

09 10

Which biosimilars are currently available in Europe?

So far, the European Union has approved 7 biosimilars, across 3 product classes: human growth hormones,erythropoietins and granulocyte colony stimulating factors.

What about the rest of the world?

In the United States, theBiologics Price Competition andInnovation Act, signed into law inMarch 2010, created a statutoryframework for the approval ofbiosimilars by the Food and DrugAdministration (FDA). Almost allguidelines that have either beenpassed or are being discussed inother parts of the world (forexample Australia, Japan, Korea,Malaysia, Mexico, Switzerland,South Africa, Taiwan and Turkey)largely correspond to theEuropean body of regulations forbiosimilars. Lastly, the WorldHealth Organisation’s guidelinefor biosimilars fundamentally follows the EU principles and ismeant to serve as a basis forcountries to develop their ownbiosimilar legislation.

What does the entry ofbiosimilars in the marketmean to originator products?

Market success for all medicines,including biological medicinesand biosimilars, in the EUdepends upon a number of factors, including pricing andreimbursement and physician and patient expectations.

Biosimilar products compete with originator biologicals, whichalready compete with other originator products made by different biopharmaceutical companies. Experience so farindicates that biosimilar uptakevaries by product class and country. Naturally, biosimilars are versions of older biologicalmedicines that have lost IP protection. Continued innovation

has often led to second-generation biological medicinesproviding increased therapeuticbenefits to patients. This meansthat the biosimilar productsmainly compete with older biological medicines, with whichthey are comparable, rather thanwith the most recent innovativetreatments.

Over the last 2 years, the biosimilar market shares havesteadily increased in most countries. In several Europeancountries, biosimilars now have ahigher volume market share thanthe reference products, and thistrend appears to be accelerating.

Name

AbseamedBinocritBiograstim

Epoetin alfa HexalFilgrastim Hexal

Filgrastim ratiopharmNivestim

Omnitrope

Ratiograstim

Retacrit

Silapo

Tevagrastim

ValtropinZarzio

Date of authorisation

28/08/200728/08/200715/09/2008

28/08/200706/02/2009

15/09/2008

08/06/2010

12/04/2006

15/09/2008

18/12/2007

18/12/2007

15/09/2008

24/04/200606/02/2009

Status

AuthorisedAuthorisedAuthorised

AuthorisedAuthorised

Authorised

Authorised

Authorised

Authorised

Authorised

Authorised

Authorised

AuthorisedAuthorised

Active substance

epoetin alfaepoetin alfafilgrastim

epoetin alfafilgrastim

filgrastim

filgrastim

somatropin

filgrastim

epoetin zeta

epoetin zeta

filgrastim

somatropinfilgrastim

Therapeutic area

Kidney Failure, Chronic Anemia CancerKidney Failure, Chronic AnemiaHematopoietic Stem Cell TransplantationNeutropenia CancerKidney Failure, Chronic Anemia CancerNeutropenia Cancer Hematopoietic StemCell TransplantationNeutropenia Hematopoietic Stem CellTransplantation CancerHematopoietic Stem Cell TransplantationCancer NeutropeniaTurner Syndrome Dwarfism, Pituitary Prader-Willi SyndromeNeutropenia Cancer Hematopoietic StemCell TransplantationCancer Anemia Kidney Failure, ChronicBlood Transfusion, AutologousAnemia Blood Transfusion, AutologousCancer Kidney Failure, ChronicNeutropenia Cancer Hematopoietic StemCell TransplantationDwarfism, Pituitary Turner SyndromeCancer Hematopoietic Stem CellTransplantation Neutropenia

For patients

Patients need and deserve to befully informed about any medicaltreatment that they are receiving.If a physician chooses to prescribea medicine to a patient, thepatient should be involved inthat decision, meaning that thepatient understands why thechoice has been made as well

as what it will mean for his orher treatment.

Patients may not be completelyaware of the complexities of biologicals, including biosimilars,and the implications of usingthem. This includes the potentialof different products to provokedifferent immunogenic reactionsin the patient. It is importantthat patients are not obliged to"switch" their treatment fromone biological to another purelyon cost grounds, the specifictherapeutic needs of the patientmust always be taken intoaccount.

According to a survey by theInternational Alliance of Patients'Organizations (IAPO), the keyinterests of patients with regardsto biosimilars are:

Cost and the potential toincrease access to biologicaltreatments;Safety and efficacy;Patient information and decision-making;Regulatory process; andInterchangeability.

Therefore, it is very importantthat the label and other productinformation relating to the biosimilar reflect the specificcharacteristics (such as reference product, potential side effects etc).

For healthcare professionals

Healthcare professionals need to understand the EMA approvalprocess for biosimilars and beaware of the scientific dataunderlying their approval (in particular the abridged clinicaldata requirements, which canallow the extrapolation of indications).

For physicians too, it is veryimportant that the label andother product information relating to the biosimilar reflectthe specific characteristics (suchas reference product, potentialside effects, etc). The summaryof product information on biosimilars should also list theavailable data in order to show which applications weresubstantiated by studies andwhich were derived from thebiological medicine of the original manufacturer withoutseparate data via extrapolation.

Furthermore, healthcare professionals must be aware thatthe interchangeability betweenthe biosimilar and its reference

product has not been evaluatedby the regulatory authority.Physicians should not be obligedto prescribe a certain medicationpurely on the grounds of cost, butshould be allowed to exerciseappropriate clinical judgment.

With regards to patients, it isvery important for healthcareprofessionals that the label andother product information of the biosimilar reflect its specificcharacteristics (clinical data, reference product, etc.).

For payers

Payers, such as national healthsystems and health insurancefunds, are interested in the cost-saving potential of biosimilars.Biological medicines havebrought great benefit to patients,often treating so far untreatableor insufficiently treatable, severediseases. Biosimilars offer oppor-tunities for savings upon loss ofIP protection for the originatorproducts. Biosimilars havebrought enhanced competition to prices of biological medicines,which in turn have resulted insignificant price decreases in themajority of markets. It is impor-tant however that physicians andpatients retain the flexibility tomake informed decisions aboutthe different treatment options.

It is important that payersunderstand that, due to the precautionary principle, automatic substitution for biologics should not occur andthe choice to use any biologicalproduct should remain in thehands of the treating physician.Any future decisions need to bebased on appropriate data. Thephysician must be allowed toexercise appropriate clinicaljudgment to select the best avai-lable treatment for the individualpatient, and such choices shouldnever be mandated purely onthe basis of product prices.

the specific therapeutic needs of the patient mustalways be taken into account.

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Source: European Medicines Agency (June 2011)

GLOSSARY OF KEY TERMS REFERENCES

Biological Medicines A Focus on Biosimilar Medicines

11 12

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Article 10.

Available at: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:32001L0083:en:NOT

Brochure - Biosimilar medicinal products; 2001;European Medicines Agency.

Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Brochure/2011/03/WC500104228.pdf

Questions and Answers on biosimilar medicines (similar biological medicinal products); Oct 2008; European Medicines Agency.

Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf

All the following European Medicines Agency’s guidelines are available at:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/ special_topics/document_listing/document_listing_000318.jsp&murl=menus/special_topics/special_topics.jsp&mid=WC0b01ac0580281bf0

Guidelines on Similar Biological Medicinal Products containingBiotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues; Feb 2006; EuropeanMedicines Agency

Concept paper on the Revision of the guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality Issues; Feb 2011;European Medicines Agency

Guidelines on Similar Biological Medicinal Products ContainingBiotechnology-Derived Proteins as Active Substance: QualityIssues; Feb 2006; European Medicines Agency

Guidelines on Similar Biological Medicinal Product; Sep 2005; European Medicines Agency

Guidelines on Similar biological medicinal products containingrecombinant follicle stimulation hormone; Mar 2010; European Medicines Agency

Guidelines on Similar biological medicinal product containing recombinant interferon beta; Mar 2010; European Medicines Agency

Concept Paper on Guidelines on Similar biological medicinalproducts containing monoclonal antibodies; Nov 2010;European Medicines Agency

Guidelines on Similar biological medicinal products containing recombinant Erythropoietins; Sep 2010; European Medicines Agency

Guidelines on Similar biological medicinal products containing low-molecular-weight-heparins; Oct 2009; European Medicines Agency

Guidelines on Non-clinical and clinical development of similar medicinal products containing recombinant interferonalpha; Apr 2009; European Medicines Agency

Guidelines on Evaluation of Similar Biotherapeutic Products(SBPs); Oct 2009; World Health Organization (WHO).

Available at: http://www.who.int/biologicals/areas/biological_ therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf

CPME Position on Access to Medicines – Biosimilars; Mar 2011; Comité Permanent des Médecins Européens.

Available at: http://cpme.dyndns.org:591/database/2011/cpme.2011-027.Position.Biosimilars.pdf

Biosimilar Medicines; International Alliance of Patients’Organizations; May 2006.

Available at: http://www.patientsorganizations.org/showarticle. pl?id=727;n=37120

Advanced therapies: New and emerging therapies, including cell,gene and tissue therapies

Adverse event: The occurrence of an undesirable, unpleasant or life-threatening reaction to a medicinalproduct

Amino acid: Building block of proteins. There are 20 common amino acids found in proteins

Antibody (pl: antibodies): Antibodies(also known as immunoglobulins,abbreviated to Ig) are proteins that arefound in blood or other bodily fluids.Antibodies are used by the immunesystem to identify and neutralise foreignobjects, such as bacteria and viruses

Autoimmune disease: A disease caused by the body producing anexcessive immune response against its own tissues. Thereby, the immunesystem ceases to recognise one ormore of the body's normal constituentsas "self" and will create auto-antibodiesthat attack its own cells, tissues,and/or organs. Inflammation and tissuedamage are common symptoms ofautoimmune diseases

Automatic substitution: The practiceby which a product other than the one specified on the prescription isdispensed to the patient, without theprior informed consent of the treatingphysician. A variation of substitution ispracticed in some countries, where, ifthe physician prescribes by InternationalNon-proprietary Name (INN), the pharmacist may decide to dispense anyproduct with the same active ingredient

Biological/biotech medicine:A medicinal product or a vaccine thatconsists of, or has been produced bythe use of, living organisms. Oftenrecombinant DNA (a form of DNA thatdoes not exist naturally and whichcombines DNA sequences that wouldnot normally occur together in orderto establish new functions) forms the basis for biotechnologically manufactured products. Examplesinclude therapeutic proteins such asantibodies, insulins or interleukins; butalso vaccines, nucleic acid or tissuesand cells. For the purpose of this document, the term “biological/biotechmedicine” refers to therapeutic proteins

Biosimilar: A similar, but not identical,version of an existing biological

medicine made following the patentexpiry of the original product (must bemade by a different manufacturer)

Biotechnology: Any technologicalapplication that uses biological systems,living organisms, or derivatives thereof,to make or modify products or processes for specific use

Cell line (including master cell line):A well-established, living system of cultured (grown in a laboratory) cellsthat will continue to grow and producenew cells indefinitely, so long as thecells receive nourishment and havespace to propagate

Extrapolation: Extending the findingsfrom one set of conditions to another,such as extending and applying thedata from clinical studies regardingone medical condition to anothermedical condition or extending datafrom clinical studies in adults to children

Generic (medicine): A copy of anexisting (chemical) medicine, which isbioequivalent to the original medicine,but which may be made by a differentfirm after patent expiry of the originatorproduct

Immune system: The collection ofmechanisms within the body that protect against disease by identifyingand killing pathogens (e.g. viruses and bacteria) and tumour cells

Immunogenic: The potential to causeimmune reactions

Indication: The medical condition,disorder or disease for which a certaintest, medication, procedure, or surgeryis used. Such tests and medications are often subject to official (regulatory)approval. Most countries and juris-dictions have a licensing body whoseduty it is to determine whether toapprove a drug for a specific indication,based on the relative safety of thedrug and its efficacy for the particularindication (use) being investigated

INN: International Non-proprietaryName

Interchangeability: Where two products can be exchanged one withanother without a significant risk of an adverse health outcome

Marketing authorisation: The permission granted by a regulatoryauthority to a company to market amedicinal product in accordance with

the conditions described in the label,following the company's submission of required documentation and datarelating to testing and clinical trials ofthe product

Molecule: The smallest particle of asubstance that has all of the physicaland chemical properties of that substance. Molecules are made up ofone or more atoms. If they containmore than one atom, the atoms can be the same (an oxygen molecule hastwo oxygen atoms) or different (awater molecule has two hydrogenatoms and one oxygen atom).Biological molecules, such as proteins,can be made up of many thousands of atoms

Molecular: Of a molecule

Nucleic acid: A macromolecule (i.e. a very large molecule) composedof chains of monomeric (having a singlecomponent) nucleotides, which aremolecules that, when joined together,make up the structural units of RNAand DNA. In biochemistry these molecules carry genetic information or form structures within cells

Patent: A patent is a set of exclusiverights granted by a state (nationalgovernment) to an inventor or theirassignee for a limited period of time in exchange for public disclosure of aninvention. Typically, however, a patentapplication must include one or moreclaims defining the invention whichmust be new, non-obvious, and useful or industrially applicable

Pharmacovigilance: Safety controlprocedures to which medicines aresubject before, during and after theirapproval by regulatory authorities

Protein: Large organic compoundsmade of amino acids. Proteins areessential parts of organisms and participate in virtually every processwithin cells

Reference product: The original product to which a biosimilar or generic drug refers in its applicationfor marketing approval

Vaccine: A biological preparationwhich is used to establish or improveimmunity to a particular disease