Potential impact of subsequent entry biologics in nephrology practice in Canada

16 Pages·2015·0.67 MB·English

Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32
DOI10.1186/s40697-014-0032-7
REVIEW Open Access
Potential impact of subsequent entry biologics in
nephrology practice in Canada
Daniel J Martinusen1,4*, Clifford Lo1, Judith G Marin2, Nicole W Tsao3 and Marianna Leung2
Abstract
Purpose ofreview: Subsequententry biologics may soon be a reality inCanadian nephrology practice. Along with
opportunities to reduce health care costs, theseagents pose unique challenges thatmust be met for successful
implementation. Understandingtheexperiences around theglobe inboth regulatory affairs and implementation
will be a valuable guide for Canadian clinicians. This report provides an executive summary ofthe information
required to guide decisions to use or implement subsequententry biologics by comparing Canadian regulations to
other developed nations, discussing their clinical issues and predicting their impact on theCanadian market and
nephrology practice.We hope that this review will assist clinicians and policy makersto navigate this complex
subject and to make informed decisions in thebest interest oftheir patients.
Sources ofinformation: Sources of information include publishedliterature and reports available inthe public
domain including guidelines obtained from regulatory agencies and informationsharedby Pharmaceutical
companies. Lastly, wegenerated informationfrom our own focus group consisting ofnephrologists, a regulatory
body representative,a hospital formulary representative, a patient representative, a hospital administrator, and a
health economist.
Findings: There existsa common and robust approach in theG20 countries for approval and regulation of
subsequent entry biologics.Althoughby definitionthese agents do not have advantages(other than costs) or
disadvantages compared to the original biologic, thereare potentialconcerns and economic uncertainties
regarding their implementation. WhereSEBs are onthe market, theirmarketshare is variable and modest.
Limitations: We did notpurchase third party reportsfor up to theminutemarketing data. Since thereare no
subsequent entry biologics currently onthe Canadian market,the information is only predictive.
Implications: The nephrology communitywill have to work withpatients, payers, and regulatory bodies to ensure
safe and effective use of subsequent entry biologics.Cost savings can be achieved but theseagentsshould only be
used after fully understanding their unique challenges. Atthis time, theyshould not be automatically substitutable
and only used for Health Canada-approved indications. Only through goodpharmacovigilence will health care
providers and patients become better informed.
Keywords: Subsequent entry biologics, Biosimilars,Biotherapeutic products, Biologics, Nephrology, Regulation
*Correspondence:[email protected]
1BritishColumbiaProvincialRenalAgency,Vancouver,Canada
4RoyalJubileeHospital,IslandHealthAuthority,1952BayStreet,Victoria,
BritishColumbiaV8R1J8,Canada
Fulllistofauthorinformationisavailableattheendofthearticle
©2014Martinusenetal.;licenseeBioMedCentral.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycredited.TheCreativeCommonsPublicDomain
Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle,
unlessotherwisestated.
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page2of16
ABRÉGÉ
Objectif de larevue:L’utilisationdesproduitsbiologiquesultérieurspourraitbientôtdevenirréalitéennéphrologie
auCanada.Cesagents,quipermettentpossiblementdesréductionsdecoûtsensoinsdesanté,présententdesdéfis
particuliersquidoiventêtreévaluéspouruneintroductionréussiesurlemarché.Àceteffet,arriveràcomprendre
lesdifférentesexpériencesquisesontdérouléespartoutdanslemondeenmatièrederéglementationetdemise
enœuvredecesagentsestunexerciceprécieuxquipourraitguiderlespraticienscanadiens.Cerapportfournitun
résumédesinformationsrequisespourguiderlaprisededécisionpourl’utilisationetl’introductiondesproduits
biologiquesultérieurs:comparaisondesréglementationscanadiennesàcellesd’autrespays;discussiondesenjeux
cliniquesentourantlesproduitsbiologiques ultérieurs et prévision de l’impact de leur utilisation sur le marché
canadien et sur la pratique de la néphrologie. Nous espérons que cette revue aidera les cliniciens et les
décideurs dans l’exploration de ce sujet complexe et dans une prise de décision optimale pour leurs patients.
Sources d’information: Plusieurs sourcesd’informationontétéutilisées,dontdespublicationsetdesrapportsdu
domainepublic,souslaformedelignesdirectrices d’organismes de réglementation et de documents provenant
de compagnies pharmaceutiques. De plus, nous avons utilisé l’information générée par notre propre groupe
de discussion. Ce dernier est composé de néphrologues, d’un représentant d’organisme de réglementation,
d’un représentant de la Liste des médicaments des hôpitaux, un représentant des patients, d’un directeur
d’hôpital et d’un économiste de la santé.
Résultats: Dans les pays membres du G20, il existe une approche robuste communément adoptée pour
l’approbation et la réglementation des produits biologiques ultérieurs. Par définition, ces agents ne présentent
aucun avantage (sauf économique),ou désavantage particulier lorsqu’on les compare aux produits biologiques
originaux, mais certaines préoccupations persistent quant à leur introduction sur le marché. Par ailleurs,
lorsque les produits biologiques ultérieurs sont disponibles sur le marché, leur part de marché reste modeste
et variable.
Limites de l’étude: Nous n’avons pas fait l’acquisition de rapports en provenance de tiers contenant des
données de commercialisation récentes. De plus, puisqu’il n’existe pas de produits biologiques ultérieurs sur le
marché canadien à l’heure actuelle, l’information de cette revue n’est que de nature prédictive.
Implications: L’ensemble desnéphrologuesaurontàcollaboreraveclesorganismesderégulation,lespatients,etles
contribuablesafind’assureruneutilisationefficacedesproduits biologiques ultérieurs. Des économies peuvent
être réalisées, mais ces agents ne devront être utilisés qu’après avoir tout à fait compris les défis particuliers
qu’ils présentent. En ce moment, ils ne peuvent pas remplacer automatiquement d’autres produits et ne
devraient être utilisés que selon les recommandations officielles de Santé Canada. Ce n’est qu’en exerçant une
bonne pharmacovigilance que les patients et prestataires de soins de santé deviendront mieux informés.
What was known before in the near term, these decisions will determine the allo-
Epoetin biosimilars (also known as subsequent entry bi- cation of hundreds of millions of dollars. This report
ologics in Canada) have been marketed in Europe since shouldassistinmakingtheseimportantdecisions.
2007 and will enter the Canadian market in the near fu-
ture. The reason for using these agents is their reduced Key messages
cost. Subsequent entry biologics should not be thought of as
generic versions of the innovator biologic and therefore
What this adds decisionstousethemarenotstraightforward.Unlikegen-
This paper provides an executive summary of the infor- eric medications, Health Canada considers subsequent
mation required to guide decisions to use or implement entry biologics to be not interchangeable or substitutable
subsequententrybiologicsbycomparingCanadianregu- with the innovator product. The use of subsequent entry
lations to other developed nations, discussing their clin- biologics should be a therapeutic decision made in con-
ical issues and predicting their impact on the Canadian sultationwithaphysician.
market andnephrology practice.
Implications for future research/policy
Why this report is important In addition to financial variables, key policy decisions
The Canadian nephrology community will have to make shouldtake into considerationphysician, pharmacist and
decisions regarding to use of subsequent entry biologics patient preferences such as those that can be elicited
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page3of16
through discrete choice experiments. Policies influence InordertodevelopanapproachtoSEBs, weundertook
nephrology should also be made in partnership with an extensive environmental scan, including an under-
other medical specialties who use subsequent entry bio- standing of the current (2013 to 2014) worldwide use of
logics, with all parties cognizant of their impact on the SEBsas wellas nationaland international regulationsand
majority payer and to make decisions that will result in policies. Using this multi-pronged approach, we are able
thegreatestbenefittothehealthcare system. to present for the nephrology community, a synthesis of
key points required to understand the issues, as well as
Introduction recommendations for moving forward as a responsible
Biologic medicines have contributed to the health of communityofcareprovidersinnephrology.
Canadianssincethe1980sandtheofferingsofthesecom-
plextherapieshaveexpandedgreatly.Originallyconsisting Review
of proteins of varying lengths, biologics introduced re- ClinicalissuesregardingSEBs
cently tend to be very large monoclonal antibodies with As a concept, SEBs have no advantage (other than cost)
very specific targets. These innovations to health, while or disadvantage over the reference biologic. Nonetheless,
welcomed, have come at great financial expense. As the their introduction to the market place will have a num-
patentsexpireformanyoftheseproductswithinthisdec- ber of benefits linked to other positive outcomes. As the
ade,thereareopportunitiesforacompetitivemarketplace price of biologics fall, more patients may be offered the
to reduce these costs by marketing “copies” of innovator treatment and/or the treatment may be offered earlier in
biologics called subsequent entry biologics (SEBs). In the course of the disease. In other contexts where ex-
Canada,SEBsaredefinedby Health Canada as biologics pandeduseofanagentmaynotbeapplicable,forexample
that are similar to, and would enter the market sub- with respect to erythropoiesis stimulating agents (ESAs)
sequent to, an approved innovator biologic. However, for the treatment of anemia of chronic kidney disease
unlike small-molecule generic medicines, production of (CKD), reduced acquisition costs will be realized by the
biological molecules is complex and exact copies cannot healthpayer(increaseefficiency),andmaybeusedtofund
be produced. SEBs are derived by complex living sys- other aspects of care. Increased competition in Canada
tems and are comparatively much larger molecules than may incent provisions of additionalvalue,such as making
thetraditionalsmallmolecules:aspirin, for instance, has better deliverydevices, training, education and other sup-
a molecular weight of 180 daltons [1], compared with port services for patients and caregivers. System-wide,
erythropoietinat30,400daltons[2],andmonoclonalanti- they may improve reimbursement and third-party payer
bodiesat150,000daltons[3]. support in addition to the education and clinical data
Themanufactureofsmallmoleculesfollowsawell-defined neededbyclinicians.
and reproducible chemical synthesis for which the result- Another potential benefit will be the drive to innovate
ing product can beeasily compared tothe innovator with (to retain market share) by developing second or third
about50tests[4].Bycomparison,theSEBistheresult of generation biologics. Innovator companies can extend
a carefully and tightly controlled biological process where the half-life of a biologic, increase potency, reduce tox-
there may be as many as 200 complex comparative tests icity and immunogenicity or improve the method of ad-
[4,5]. Given that these proteins are derived from complex ministration. Humanization of biologics will likely be an
living organisms, the resulting structure can never be important goal to further improve current offerings. For
identical to the innovator or “reference” biologic. There- anemia, novel erythropoietin receptor agonists are being
fore, it is important to strike the right balance between developed. Companies will be invested in this develop-
maintaining the safetyand effectivenessCanadians expect ment as regulators will extend the patent life on the
and deserve, reducing costs and encouraging innovation drug or if deemed a new drug, the company will get sig-
forbettertherapies. nificantmarketexclusivity.Overthelong term,therapies
This paper serves as an executive summary of the work forCanadianswillcontinuetoimprove.
undertakenbyanindependentgroupofpharmacists,atthe However,SEBsarenotwithoutrisks.Immunologicalre-
request oftheCanadianSocietyofNephrology,toevaluate actionstoabiologicdrugareamongstthemostimportant
the impact ofSEBs on Canadian nephrology practice. A adverse reactions that are possible. While reactions can
full textoftheoriginalreportisavailableontheCanadian be simply developing antibodies with no clinical conse-
SocietyofNephrologywebsite,andthispaperservesasan quences, antibodies themselves can result in systemic im-
executive summary of the project, discussing main issues munereactions,autoimmunitytoendogenousproteinsor
andkeyrecommendations.Inaddition,afullsystematicre- the undermining of therapeutic efficacy through anti-
view of safety and efficacy as well as an economic analysis bodies targeting endogenous proteins [6]. Nephrologists
of epoetin SEBs in Canada was undertaken; these are pre- arewell awareofPRCAthatoccurredas aresultofafor-
sentedinseparatepublicationsandalsointhefullreport. mulation change of Eprex® introduced years after original
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page4of16
marketing, despite the comparability exercises performed. becoming similar and strike a balance between scientific
The manufacturer changed the processing of the rubber comparability, sound safety and efficacy testing while
intheprefilledsyringeand the formation of polysorbate creatingalesscostlypathwaytoapproval.
80 micelles containing proteins. This then influenced China, Russia and Thailand are the exceptions. China
the formation of aggregates/impurities and resulted in has had no biosimilar pathway and has treated each sub-
increased immunogenicity expressed as pure red cell mission as a new drug. China is actively working toward
aplasia(PRCA)[7].Hence,aproductinuseforyearswith a biosimilar pathway and has indicated that the creation
agoodsafetyrecordwasunfortunatelyresponsibleforser- of a strong biologic sector is one area of focus over the
ious side effects, due to a change in the manufacturing comingyears.
process. Similar concerns were raised for the biosimilar A comprehensive review of the different world wide
epoetin HX575 in trial data and it remains indicated regulatory approaches is available in our full report; the
for only theintravenousroute,howeverstudiesonthisare following summarizes the leading regulatory frameworks
ongoing. Our independent systematic review and meta- that exist. The reader should be aware that SEBs have
analysisfoundlittledifferenceinsafetyandefficacybetween different names in other countries such as biosimilars
epoetinSEBsandtheirreferencebiologic.Yet,PRCAhigh- according to the European Medicines Agency, or similar
light the importance of comparability studies as well as biotherapeutic product according to the World Health
strongpharmacovigilenceprograms[8]. Organization. Despite differences in nomenclature, simi-
Biologic drug manufacturers over time have made larprincipalsapply ascan beseeninTable1.
changes to the way each biologic is manufactured to im-
prove efficiency or quality or both [9]. With each change, HealthCanada
the resulting product must be compared to the molecule TheapproachtoSEBstakenbyHealthCanadaisconsistent
before the change. The manufacturer works with the na- withthatoftheEMAandtheWHO;sponsorsareevenre-
tional regulatory body to conduct an internationally stan- ferred to the EMA product class specific guidance docu-
dardized comparability exercise to ensurethat the change ments (for instance, epoetin, G-CSFand growth hormone)
has not adversely affected the product safety or efficacy becauseofthesimilaritiesinscientificprinciples[14].
[10,11]. Testing for immunogenicity is an important as- SEBs are approved through the New Drug Submission
pectofcomparinganSEBtoareferenceproductaswellas pathway in Canada. This pathway requires the SEB spon-
comparingabiologicpre-andpost-manufacturingchange. sor to submit a full chemistry and manufacturing data
These PRCA incidents warrant a better understanding packageinadditiontoextensivedatademonstratingsimi-
of PRCA pharmacoepidemiology, the risk chain of anti- larityoftheSEBwiththereferencebiologic.Thisincludes
erythropoietin antibody development, consistency in the characterization studies conducted in a side-by-side for-
assay used, a validated serum-cut-off value and differenti- mat to determine physiochemical properties, biological
ation between neutralizing antibody to PRCA develop- activity, immunochemical properties, purity, impurities,
ment [7]. Health Canada directs that to study the safety contaminants, and quantity [12]. The demonstration of
and efficacy of the product, validated methods should be similaritydoesnotsignifythatthequalityattributesofthe
used to characterize the antibody content (concentration SEB and the reference biologic being compared is identi-
or titre) and the types of antibodies (neutralizing or cross cal,butthattheyarehighlysimilarwiththefollowingtwo
reacting) [12]. Unfortunately such a change may not be consequences[12]:
detecteduntilithaswidespreaduse.
Thecomparabilityexercisesforamanufacturingchange 1. Theexisting knowledgeof bothproductsis
toanoriginatorbiologicformsthebasisfortheregulatory sufficienttopredict thatanydifferencesinquality
framework of SEBs to ensure they are safe and effective. attributesshouldhavenoadverse impact upon
The goal is to safely bring a similar enough biologic to safety orefficacy oftheSEB.
market at a reduced cost to both the manufacturer and 2. Non-clinical andclinicaldatapreviously generated
theconsumerwhilemaintainingefficacy. with thereferencebiologicdrugarerelevanttothe
SEB.
Regulatory agencies and international approaches
The European Medicines Agency (EMA) was the first to If similarity of an SEB to the reference biologic drug
create a legal pathway for SEBs in 2005, followed by cannotbeestablishedbasedonthe chemistryandmanu-
guidelines for approval in 2006. Since then, Australia, facturingdata package,thenreduced clinicaldata cannot
Brazil, Canada, Cuba, India, Japan, Malaysia, Singapore, be justified and the product cannot be considered as an
South Korea, Taiwan, Turkey, United States and the SEB[12].
World Health Organization have all created a regulatory Any claims made by the SEB sponsor should be sup-
framework for SEBs. Guidelines around the world are ported by suitable scientific data, which typically includes
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page5of16
Table1ComparisonofrequirementsfortheevaluationofSEBsbetweendifferentregions[13]
EU Australia Japan WHO Canada Korea,India,
Singapore,Malaysia
Synonym Biosimilars Biosimilars Follow-on SimilarBiotherapeutic SubsequentEntry Biosimilars
Biologics Product Biologic
Scope Mainlyrecombinantproteindrugs Recombinantproteindrugs
Principles (cid:129)GenericapproachisnotappropriateforSEB.
(cid:129)SEBshouldbesimilartothereferencebiologicwithrespecttoquality,safetyandefficacy.
(cid:129)Step-wisecomparabilityapproach:thereductionofnon-clinicalandclinicaldatarequiredwillonlybeconsidered
afterthesimilarityoftheSEBandreferencebiologicisprovenintermsofquality.
(cid:129)Casebycaseapproachfordifferentclassesofproducts.
(cid:129)Pharmacovigilanceisstressed.
Referenceproduct AuthorizedintheEU Authorizedin Authorizedinaregionwithawell-establishedregulatory
Japan framework
Manufacture (cid:129)Samestandardsrequiredbythenationalregulatoryagencyfororiginatorproducts.
(cid:129)Fullchemistryandmanufacturedatapackage.
Physio-chemical (cid:129)Primaryandhigher-orderstructure.
(cid:129)Posttranslationalmodifications.
Purity (cid:129)Process-relatedandproduct-relatedimpurities.
Nonclinical (cid:129)In-vitrosuchascell-basedassaysandreceptor-bindingstudies.
Stability Accelerateddegradationstudiesand Not Accelerateddegradationstudiesandstudiedundervariousstress
studiedundervariousstressconditions necessary conditions
Pharmacokineticstudy (cid:129)Singledose,steady-statestudiesorrepeateddeterminationsofpharmacokinetics
design&criteria
(cid:129)Crossoverorparallel.
(cid:129)Includeabsorptionandeliminationcharacteristics.
(cid:129)Usethetraditional80-125%equivalencerange.
PD Pharmacodynamic(PD)markersshouldbeselectedandcomparativePK/PDstudiesmaybeappropriate
Efficacy Comparabilitymarginsshouldbe Observerordouble-blinded. Equivalence
pre-specifiedandjustified Equivalenceornon-inferiority
Safety/ (cid:129)Pre-licensingsafetydataandriskmanagementplan.Postauthorizationsafetyand/orefficacystudiesmayberequired.
pharmacovigilance
(cid:129)Adversereactionsmustbereported.
(cid:129)SamerulesapplytoreferencebiologicandSEB.
INNvs.newgeneric INN Uniquegenericname Suffix“BS” INNwithbiological INNbutwillfollow INN
name addedtoINN qualifier(proposed) WHOguidance
Extrapolation (cid:129)Assessedonacase-by-casebasis.
ofindications
(cid:129)Atleastoneclinicalstudyrequiredinthemostsensitivepopulationmeasuringtheclinicalendpointslikelyto
showadifference.
Adaptedfrom[13].
safetyandefficacydataaswellascomparativepharmacoki- and in certain cases it may be possible to extrapolate
netic(PK)/pharmacodynamic(PD)studies[12].Asforeffi- clinical data to other indications where rationales are
cacy and safety studies, head-to-head equivalence trial(s) sufficiently persuasive [12]. The decision is based on
arepreferredastheydefineupperandlowercomparability mechanismofaction, diseasepathophysiology, safetypro-
margins.Theregulatoryagencymayacceptnon-inferiority file and clinical experience [12]. Recently, Health Canada
trials,whichdescribeonlythelowerefficacymargin.Stud- granted limited extrapolation of indications to the SEB
ies may not be deemed to provide strong enough support infliximab [15]. Of the 50 countries granting approval to
forextrapolationtootherindicationsapprovedfortheref- the biosimilar infliximab, only Japan and Canada limited
erencebiologic,particularlyiftheotherindicationsinclude theindicationscomparedtotheinnovatordrug.
different dosages than those tested [12]. However, add- Although SEBs must demonstrate similarity to the ref-
itional indications may be granted to the SEB in the ab- erence biologic, they are approved as a new drug and
sence of clinical data with only comparative PK/PD data therefore they are not declared to be pharmaceutically or
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page6of16
therapeutically equivalent to their reference biologic ac- manufacture, import or distribute to the Canadian public
cording to Health Canada [14]. Unfortunately, specialized [16]. It is mandatory for market authorization holders to
studiessupportingtherapeuticinterchangearenotusually report adverse drug reactions (ADRs), notify the Minister
done and their relevance may not be long lasting due to ofHealthofasignificantchangeinaproduct’sbenefit-risk
manufacturingchangesovertime[14]. Itisforthisreason profile and provide an overall safety evaluation of the
that Health Canada does not support automatic substitu- product in the form of an annual summary report [16].
tionandrecommendsphysiciansmakewellinformeddeci- Consumers, patients and health professionals are also en-
sions regarding therapeutic interchange [14]. Admittedly, couraged to report adverse reactions through MedEffect™
theauthoritytodeclaretwoproductsautomaticallysubsti- Canada[16].Lastly,HealthCanadaiscommittedtoalign-
tutablebyapharmacistdoesnotrestwiththefederalgov- ing with international best practices and standards in-
ernment, but Health Canada’s position and regulatory cluding commitment to full integration of International
processshouldinformdecisionsregardinginterchangeabil- ConferenceonHarmonizationvigilancetools[16].
ityandsubstitutability[14].
RecognizingCanadarepresentsasmallportionoftheglo- WorldHealthOrganization
bal market share for biologic medications, Health Canada The WHO has served to harmonize the biologic medi-
has taken the WHO position that differs from the EMA, cine regulation worldwide and is well placed to do so for
the United States FDA, the Australian Therapeutic Goods biosimilars. In seeking common ground amongst coun-
Administration and the Japanese Pharmaceutical and tries, it must also allow for variability where there is cur-
Medical Devices Agency, by allowing the “reference bio- rently debate. Hence, while the EMA is quite specific, the
logic”(towhichtheSEBiscompared)tobeaproductthat WHO guidelines are replete with “should” statements in
is not authorized for sale in Canada. If a non-Canadian comparison.Thatbeingsaid,theWHOdidrelyheavilyon
reference biologic is used, certain criteria must be met the EMA guidelines to create an international standard
suchas[12]: sincetheEMAhasthemostadvancedregulations.
Like the EMA, the WHO shares the key principles of a
(cid:1) Thesponsorisresponsibleforshowing thatthe stepwiseapproachtodetermine the quality attributes of a
non-Canadianreferencebiologicisa suitableproxy product followed by non-clinical and clinical studies. The
forthe versionofproductapprovedinCanada. quality studies need to demonstrate a consistent and ro-
(cid:1) Thesponsorhastheresponsibility ofensuringthat bust production, a complete characterization of the prod-
the chosen non-Canadianreferencebiologicdrug uct and a complete comparability exercise. Only thenwill
hasassociatedwith it sufficientinformation and data a regulator consider a reduced data requirement for the
tosupportthe submission non-clinicalandclinicaldevelopment.Finally,theamount
(cid:1) Thenon-Canadian referencebiologicdrugisfrom a ofdatainthenon-clinicalandclinicalportionsofthesub-
jurisdictionthathasanestablishedrelationshipwith mission is dependent on the therapeutic class of biologic
Health Canada. andsoconsideredonacase-by-caseapproach.
(cid:1) The non-Canadian reference biologic is widely TheWHOguidelinesrecognizethatareferenceproduct
marketed in a jurisdiction that formally adopts forcomparisonmaynotbemarketedinallcountries,par-
InternationalConferenceonHarmonizationguidelines ticularlythosewithasmallshareoftheglobalmarket.Un-
and has regulatory standards and principles for liketheEMA,theWHOallowsforareferenceproductto
evaluationofmedicines,post-marketingsurveillance beusedthatismarketedoutsidethejurisdictionofthena-
activities and approach to comparability that are tional regulatory agency. The reference should have been
similar to Canada. marketedforasufficientamountoftimeandinsignificant
(cid:1) Ifthe non-Canadianreferencebiologic isusedin volume as well as having been licensed on full quality,
clinicalstudiesinCanada,data mustbeprovided to safety and efficacy data. Additionally, the WHO, like the
satisfy chemistry andmanufacturinginformation as EMA, directs that the same reference should be used
perC.05.005oftheFood andDrugRegulations. throughout the comparison and that the SEB should be
thesameinsubstance,dosageformandrouteofadminis-
Lastly, the SEB sponsor must develop, maintain and im- trationasthereference.
plement a risk management plan (RMP) which provides Good Manufacturing Practices should be implemented
proposals on how to minimize any identified or potential and the “similar biotherapeutic product” should meet the
safetyrisksthroughout the life cycle of the product aswell same manufacturing standards of the national regulatory
as provide a pharmacovigilance plan which identifies agency as the reference drug. All aspects of the manu-
and characterizes known or potential safety concerns. facturing process should form part of the submission.
In Canada, market authorization holders have primary Additionally, characterization studies including higher
responsibility for the safety of any products they sell, order structure, post-translational modification, biological
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page7of16
activity, impurities, immunogenicity, accelerated degrad- Committee for Medicinal Products for Human Use. This
ation studies and studies under various stress conditions committee reviews marketing authorization applications,
shouldbeincluded. including those for biosimilars, and makes recommenda-
Non-clinical studies should be in-vitro (such as receptor tions regarding approval to the European Commission
binding) and in-vivo (such as repeat dose toxicity studies (whichformallyapprovesmedicinalproducts).
orproductneutralizingcapacity),consistentwiththeEMA The EMA recognizes it is not economical to require a
guidelines. The clinical studies begin with the PK and PD fullcommontechnicaldocument for biosimilars and thus
followed by the clinic trials for efficacy. PK equivalence reliesonacomparabilityexercisetoreducetheamountof
between the similar biotherapeutic product and the refer- data required in Modules 4 and 5. The EMA has issued
ence product is proven if it falls between 80-125%. The several guidelines on the comparability of pre- and post-
clinical trials should be randomized; well controlled manufacturing change for a given biologic drug. These
and double-blinded or at least investigator-blinded [13]. guidelines have been broadened to include comparability
Equivalence trials are preferred as they define upper and of biologics by different manufacturers (biosimilars) and
lower comparability margins. If justified, the regulatory coverquality,clinicalandnon-clinicalissues.
agencymayaccept non-inferiority trials, which describe Additionally,biologicalclass-specificguidelineshavebeen
only the lower (efficacy) margin. These clinical trials developed to inform preclinical (PD and toxicological) and
should also produce the pre-licensing and immuno- clinical(PD,PK,safetyandefficacy)studies.Theguidelines
genicity data for the submission. are subject to periodic revision as has been seen in 2008
Similar biotherapeutic product manufacturers must with the addition of the recombinant erythropoietin agent
submit a risk management plan and pharmacovigilance guideline.Morerecentlyin2013,aguidelineintroducedby
plan. It is recognized that the limited exposure in a clin- the EMA acknowledges that for a structurallymore“sim-
ical trial may not fully characterize the adverse events ple”biologicthatcanbeverywellcharacterized,anexten-
that may be experienced when marketed. With this in sive clinical programme may not be necessary since the
mind, post-marketing monitoring is an essential compo- conclusion of biosimilarity may already be convincingly
nent to ensure ongoing safe use. Lastly, the WHO states derived from the comparison of structural and functional
that interchangeability is a national decision and beyond characteristics and PK/PD studies (i.e. no remaining un-
thescopeoftheWHOguidancedocument. certainties).However,thiswouldstillnotbeapurely“gen-
eric drugs” approach because the extensive head-to-head
EuropeanMedicinesAgency comparisonofthephysicochemicalandfunctionalcharac-
In Europe, a biosimilar is a biological medicinal prod- teristics required for biosimilars is not part of the generic
uct that contains a version of the active substance of an development programme. Similarity to the reference is
already authorized original biological medicinal product important but the clinical benefit is considered proven
(reference medicinal product). A biosimilar demon- with the reference product data. The revision also ad-
strates similarity to the reference medicinal product in dresses the possibility of generic status for some biologics
terms of quality characteristics, biological activity, safety [17]. Finally, the EMA is considering a revision to the
and efficacy based on a comprehensive comparability ex- guidelineregardingqualityasitrecognizesthattheresults
ercise[17]. of the initial comparability exercise may not hold true
In 2004, the European Parliament created processes throughouttheproduct’slifecycle.
for the central authorization and supervision of medi- Fifteen biosimilar products are marketed in Europe. Of
cines, including biologics. This regulation also allowed interest to this report, five ESA biosimilars have been
for clinical data to be omitted in the case of exceptional availablesince 2007. Threeare produced inone facility in
circumstances. A legal basis for biosimilars was created southern Germany while two are produced in a northern
in 2005, which described the requirements for the mar- German plant. Other biosimilars, namely somatropin and
ket authorization application dependent on the scientific filgrastim,arealsoavailableinEurope[18].Ofnote,epoe-
and clinical data demonstrating similarity to another tintheta(Biopoin®andEporatio®)isnotlicensedasabiosi-
biological medicinal product. The European framework milarbutasanewproductsupportedbyafullapplication.
recognizesthatbiosimilarsdemonstratesimilaritybutthey
are not identical to their reference products, given the UnitedStatesFoodandDrugAgency
complex protein structure, manufacturing process and In the United States, SEBs are referred to as follow-on
final product differences. Furthermore, there is recogni- biological medications and in 2009 the FDA released a
tion that some product differences may be undetected set of draft guidance documents to reflect the country’s
for some time and may be difficult to understand. The current position on this topic [19-22]. Although similar
European framework is supported by scientific guide- to the EMA, WHO and Health Canada in many re-
lines and procedural guidance and implemented by the spects, the US is unique because the approval pathway
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page8of16
for a follow-on biological medication depends on the such as epoetin lambda (HX575), causing a significant
type of application governing approval of the originator price competition in the treatment of anemia of CKD
product, which is either a new drug application or a bio- [24]. Australia has decided to distinguish a biosimilar
logics licenceapplication. from its reference product with regards to naming; hence,
In2010, theBiologicsPrice CompetitionandInnovation thebiosimilarforepoetinalphabecomesepoetinlambdato
Act created a conceptually similar regulatory framework indicateadifferenceinitsglycosylation[28].LikeAustralia,
to the Hatch-Waxman Act allowing for an abbreviated Japan has also commercialized HX575, but has allowed it
process to approve follow-on biologics. Unlike a novel to use the same INN with an extension,i.e. epoetin alpha
biologic that must be submitted through the biologics li- BS (BS for biosimilar). In the first 12-months of its intro-
cence application pathway, an abbreviated application for duction,thisSEBwasestimatedtohavetakenaquarterof
follow-onbiologicscanbesubmittedundersection351(k) the Japanese market share [29]. Since Japan is currently
in the Public Health Service Act. For a 351(k) application theworld’ssecondlargestpharmaceuticalmarketafterthe
tobesuccessful,aclinicalstudyorstudiesarerequiredto United States, it isimportant to realize the significance of
demonstrate safety, purity and potency for one or more harmonizing its regulatory process with the EMA [30].
appropriate conditionsofuseforwhichthereferencebio- Until recently, one slight difference from the EMA was
logic is licensed. Like Health Canada, the indications for that the PMDA did not consider low molecular weight
whichafollow-onbiologicisapproveddoesnotnecessar- heparins as SEBs [31].Therefore, therehavebeena num-
ily include all of the licensed uses of the innovator refer- ber of low molecular weight heparins approved for use as
encebiologicbutcouldvarydependingoneachbiosimilar generics[31].
sponsor’s application and the extent to which the clinical
trial information supports extrapolation across multiple “Pharmemerging”countries–China,IndiaandThailand
indications. China,IndiaandThailandareallcountrieswithlargepop-
Unlike Health Canada, the FDA believes that follow-on ulationswithinwhomonlyasmallminorityareinsuredor
biologics and the reference biologic can be interchange- have the economic ability to afford standard medical care.
able (or substitutable according to Health Canada’s defin- With increasing government expenditure on healthcare
ition), meaning a pharmacist can switch to the follow-on and a disease burden that has shifted from infectious
biologic without the intervention of the prescriber. To diseases to chronic diseases, regulators in these coun-
achieve this status, the FDA requires follow-on biologic tries are faced with even more pressure than those in
sponsors to demonstrate biosimilarity, that the follow-on Canada, the United States and Europe to facilitate the
biologic can be expected to produce the same clinical re- commercializationofSEBs.Currently,ChinaandThailand
sult as the reference product in any given patient and if have not created an official SEB approval pathway. In
the follow-on biologic is administered more than once to Thailand,however,14differentepoetinSEBsaremarketed
anindividual,theriskintermsofsafetyordiminishedeffi- and all were approved using the regulatory process for
cacy of alternating or switching between the follow-on chemicalgenericswithnocomparatorstudiestotheorigi-
and the reference product is no greater than the risk of nators[32].Somearguethatwithoutdemonstratingbiosi-
usingthereferenceproductwithout suchalternation[22]. milarity, these products cannot be considered true SEBs.
With regards to pharmacovigilance, the FDA acknowl- InChina,theStateFoodandDrugAdministration(SFDA)
edges that robust postmarketingsafety monitoringisim- approvesallbiologicsas novelagentssothateventhough
portantbutgivesminimalinformationofwhatthisentails, there are products on the market with the same generic
otherthanitshouldbeproduct-specific.TheFDAencour- nameandapproved for the same indication as the ori-
ages sponsors to consult with the FDA to discuss their ginator biologic, they have lower activity, less purity and
pharmacovigilanceapproach[20]. do not meet international standards [33]. At the moment,
China has minimal expertise with biologic development
AustralianTherapeuticGoodsAdministrationandthe andalackoffacilitiesthatarecompliantwithinternational
JapanesePharmaceuticalsandMedicalDevicesAgency Good Manufacturing Practices guidelines. However,thisis
Both the Australian Therapeutics Goods Administration rapidly changing with the increasing number of Western
and the Japanese Pharmaceuticals and Medical Devices educated returnees with experience in large biotech com-
Agency (PMDA) have released their own guidelines for panies, increasing China to become a global player with
SEBs, which are virtually identical to the EMA regulatory SEBs. Since China and Thailand do not have an SEB
framework [23-26]. Having a population of just over 23 framework,pharmacovigilancefornon-innovatorbiologics
million, Australia is an even smaller market than Canada depends on existing drug surveillance systems. In China,
[24,27]. Despite this, their early and swift adoption of the surveillance systems have developed rapidly through part-
EMA guidelines without alteration provided a robust li- nershipwiththeWHOandthepharmaceuticalcompanies
censingsystemthathasresultedinthemarketingofSEBs [30]. All ADRs are reported to The National Center for
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page9of16
ADR Monitoring that consists of five divisions and a net- the EU, only 8% of the 2.3 billion dollar market was cap-
work of 32 provincial centers [30].Thailand is unique in tured by biosimilars [4]. Moreover, France and Germany
that all new drugs must undergo a mandatory safety- account for half of the EU biosimilar market. The intro-
monitoring period of approximately two years where only duction of the monoclonal antibody infliximab biosimi-
physicians in hospitals and clinics can prescribe the medi- lar marks a significant advancement into large, complex
cations and only hospital and clinic pharmacies can dis- proteins.InJanuary 2014,Remsima™(infliximabbiosimi-
pense them [30]. It is encouraged that ADRs are reported lar,Celltrion Inc.),the brandname ofinfliximab biosimi-
totheHealthProductVigilanceCenterundertheThailand lar is set to be priced 39% less than the reference brand
FDA[30]. in Norway [37]. Within the EU, there are significant dif-
UnlikeChinaandThailand,India’sregulatoryframework ferences in market forces and hence biosimilar uptake.
has evolved quickly as a result of the country’s robust bio- Moreover, biosimilars have had significant inter-country
technology sector of over 100 companies that are actively price variability, which affects comparisons. In 2009, for
engagedinthedevelopmentorproductionofcopybiother- instance, Ratiopharm’s filgrastim biosimilar in Germany
apeutic products [34]. By volume, India is the world’s 2nd was2.5timesitspriceinSpain[38].Basedonouranalysis,
largest supplier of vaccines and the 4th largest supplier of undermarketphenomenasimilartothoseseenintheEU,
pharmaceuticals. As of 2011, the country had over 16 dif- we could expect that Canadian adoption of epoetin SEBs
ferent non-innovator epoetins, one non-innovator rituxi- wouldresultin$35million(year1)to$50million(year5)
mab and one non-innovator alteplase [34]. At the time cost savings annually, with cumulative savings of $221
theseproductswereapproved,nocomparatorstudieswere million after 5 years. Below are some factors influencing
requiredandthus the commercializationoftheseproducts price.
was relatively easy. This resulted in innovator price drops
of 30 to 50%, sometimes two to three years ahead of a Payorresponses
launch of a non-innovator product [34]. However in 2012, It is useful to examine these differences and determine
the country undertook major regulatory reform to align which country’s market, summarized in Table 2 will most
withEMAstandardswiththeDepartmentofBiotechnology resembleCanadaintheyearstocome.Theuptakeof bio-
and the Central Drugs Standard Control Organization similars seems to be greatest where the payer has greater
releasing an SEB guidance document outlining regula- influence, such as in Germany, compared to where phys-
tory requirements for marketing authorization [35]. Since icianinfluencethroughprescribingandbrandloyaltydom-
then, to demonstrate biosimilarity, comprehensive prod- inate, such as in France, Italy and Spain [39]. Also worthy
uctcharacterization,preclinicalstudiesandclinicalstudies of note is that Spain and Italy were late adopters of biosi-
in comparison with a reference biologic must be under- milars which may also explain a lower market share [29].
taken [35]. Unlike Canada, SEBs can only be developed Theclassof biosimilarsisalsoimportant.Agentstypically
against anauthorized reference biologic thathasbeenap- usedshortterm(suchas filgrastim) are likely to be as-
provedinIndiaandhasbeenlicensedandmarketedforat sociated with greater biosimilar usage, while agents used
least four years with significant safety and efficacy data. long-term(suchas long-term use of a growth hormone
Thiscanbewaivedorreducedinthecasewherenomedi- in a pediatric population) is associated with slow market
cineexists,onlypalliativetherapyisavailableorintheface growth[29].
ofanationalhealthcareemergency[35]. Germany, as an early, rapid adopter, also has the high-
Since India has adopted SEB guidelines similar to the est percentage of epoetin biosimilar sales in Europe. In
EMA, a fairly vigorous pharmacovigilance plan is now the first year, 17.3% or 60 million Euros were saved with
mandatoryformanufacturersinthepost-marketingphase. epoetin biosimilar use. Germany is considered to have a
Thisincludesthesubmissionofperiodicsafetyupdatere- “mature market” for the current biosimilar offerings and
portseverysixmonths for the first two years and then thus may have maximized their market share (65% for
annually for another two years; in addition, at least one epoetin biosimilars). Several factors worth mentioning
non-comparative post-marketing clinical study focusing haveplayedarole:
on safety and immunogenicity mustbe conducted [35]. If
anyseriousunexpectedadversereactionsoccur,theymust (cid:1) Predefined quotas: In some areas in Germany
be reported to the licensing authority within 15 days of there are quotas for biosimilar prescriptions that
initialreceiptoftheinformation[35]. must be met. For epoetin, biosimilar prescriptions
must be at least of 20% and 40% of the total in
Predicting the potential Canadian market Hamburg and Berlin, respectively. Physicians may
Despite early optimistic projections of biosimilar market face fines for not meeting prescription quotas.
predictions, worldwide biosimilar sales in 2010 were This policy was a driver in the initial years, as in
$235 million of the $138 billion biologic market [36]. In most areas today the biosimilar share exceeds
Martinusenetal.CanadianJournalofKidneyHealthandDisease (2014) 1:32 Page10of16
Table2Percent(%)biosimilarshareofreferenceproductsales[14,39]
Percent(%)biosimilarshareofreferenceproductsales
Austria France Germany Italy Poland Spain Sweden UK EUtotal
Epoetin 50 11 65 7 62 16 63 9 18
Filgrastim 52 42 45 18 38 24 45 80 38
Somatropin 6 20 12 12 7 15 21 4 13
Infliximab Approvedbutnotyetmarketed
these quotas. Canada does not have such 250 million dollars, depending on the requirements for
measures [38]. clinicalstudiesandanalysis,makingdeepdiscountingun-
(cid:1) System ofreimbursement:InGermany,doctorsand likely[42,43].InformationfromEuropesuggeststhatSEBs
hospitals arepaidbasedondiagnostic relatedgroups willbepriced25to30%lowerthantheinnovatorbiologic
so regardless of treatment, funding is the same drug. Average price reductions are 23% in the EU, and
amountperpatientperdisease.Theincentivetouse 30%inJapan[38].InCanada,largebuyinggroupsororga-
biologicsthatare30%cheaperisobvioustoprescribers nizations typically purchase innovator biologics below list
andproviders.ThecentralFederalHealthcaresets price in the form of institutional pricing or value added
reimbursementrateswhichfavoursbiosimilaruse. contracts, which may include rebates, additional services
WhileCanadadoesmonitorcostsperdiagnostic orofferingsbythevendor.Assuch,theactualpricediffer-
relatedgroupsandencourageslowercosts,thereisno encewillbelessthana25%differencefromlist.Morere-
directpenalty;howevertheprincipleofefficientuse cently, two biosimilar infliximabs approved in Europe in
ofhealthcaredollarsispromotedinCanada. September2013andinCanadainJanuary2014,areantic-
(cid:1) Referencepricing: Germanyhasareference-based ipatedtobearound30%lessthanlistprice.
pricing systeminwhichthe cheapestgenericprice is Manufacturers of innovative biologics have responded
setasthereference price.Ascheapergenericsare in Europe by reducing prices. For example, Germany
introduced,thereferencepricefalls.Furthermore,a enjoyed a 13% price reduction for the innovator epoetin
recentlawallowsbiosimilarmanufacturers,providers [38,40]. Likewise, Roche reduced prices in India to com-
andhospitalstonegotiaterebatesdirectly.Hence, pete with biosimilar products there. Moreover, not only
therearemanyhealthinsurancefundsthathavea didthereferenceproductpricedrop,butpricesforsecond
majorinfluenceonmedicationspatientsreceive.The and third generation erythropoietic agents fell as well.
neteffecthasbeentohavethesamereferenceprice These competitive pricing changes have, in part, been re-
foragivenbiologicincludingitsbiosimilars.In2011, sponsible for a slow market penetration of biosimilars.
Germanyintroducedcostbenefitlegislationinwhich Hence, whether the SEB is used or not, the overall costs
drugsthathavebeendeemedtohaveadditionalvalue fortheclassofmedicationswillbereduced.
canhaveanegotiatedpricewithhealthinsurance Both the number of SEBs and SEB uptake may affect
fundswhilethosethatdonotwillbesubjecttothe the reference product price. The 2013 price of the SEB
referencebasedprice.Goingforward,biosimilars,by epoetinandthereferencedrugisnowonly1%differentin
definition,willbesubjecttoareferenceprice[40]. Germany – a country with rapid and early adoption of
epoetin SEBs and with four epoetins on the market. In
In Poland, annual national tendering with pharmaceut- Spain,arelativenewcomertoepoetinSEBsand withonly
icalcompaniesiscommonandhastheeffectofswitching two epoetinsonthemarket,thereisa30% pricedifferen-
wholepatientgroupsfromonesomatropintoanotherand tial. Italy maintains a high price (73% higher than in
thenbackagain.This large scale interchangeofabiologic Germany) for the reference epoetin with the SEBs priced
in many EU countries (such as Germany, Sweden, Spain just 15% less than the reference. Tables 3 and 4 compare
and Netherlands) is forbidden but in Poland, there have five European countries’ epoetin data comparing 2009
been no signals of problems identified including immuno- with 2013. Of note, the British Pound gained in value
genicity[41].Asaresultofthistenderingprocess,selection againsttheEuro,makingthepricecomparativelylow.
ispricesensitiveandhasfavouredSEBsasisevidencedby
themarketpenetration. Likelysubsequententrybiologiccompaniesentryintothe
Canadianmarket
Marketresponses It is possible that only established SEB companies with a
Expectedpricereductionsandinfluenceonoverallcosts track record in Europe or other highly regulated coun-
While a generic drug may cost 2 to 3 million dollars to tries will bring SEBs to Canada. As such, they will use
bring to market, the estimated cost for an SEB is 75 to their considerable experience to influence their success.