DECLARAÞIE DE CONSENS

CONSENSUS STATEMENT

ALIN NICOLESCU*, CÃLIN GIURCÃNEANU**, MIHAIL ALECU***, LAURA GHEUCA SOLOVÃSTRU****, GHEORGHE NICOLA*****,

IRINEL ANGHELUª NEDELCU******, RODICA OLTEANU*******, ANDRA OROSAN********, VIRGIL PÃTRAªCU*********, CÃTÃLIN POPESCU**********, TATIANA ÞÃRANU***********,

ANCA ZBRANCA-TOPORAª************, MARIA MAGDALENA CONSTANTIN*************

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Rezumat

Apariþia medicamentelor generice, respectiv echi-valente terapeutice ale medicamentelor inovative, în cazulmedicamentelor biologice a dus la apariþia a numeroasepuncte de vedere privind utilizarea acestora în terapeuticaa numeroase afecþiuni, inclusiv în psoriazis.

Plecând de la definiþia datã de OMS ºi EMA aproduselor biologice ºi a bioechivalentelor acestora, autoriiîºi expun punctul de vedere privind conceptul debiosimilaritate, compatibilitate, imunogenitate a unuiprodus biosimilar cu produsul inovatov de referinþã. Deasemenea este discutatã posibilitatea de extrapolare aindicaþiilor unui produs biosimilar când nu existã studiiclinice decât pentru preparatul de referinþã.

Summary

The emergence of generic drugs, meaning pharma-ceutical drugs that are equivalent to innovative drugs,resulted in numerous points of view in the case of biologicaldrugs regarding their use in the therapy of many diseases,including psoriasis.

Considering the definition given by WHO and EMAfor biological drugs and their bioequivalents, the authorsexpress their views on the concept of biosimilarity,compatibility and immunogenicity of a biosimilar product.The possibility of extrapolating the indications for abiosimilar drug when there are no clinical studies for it, isalso discussed by the authors.

* CMDT Roma, Bucureºti / CMDT Rome, Bucharest.** UMF „Carol Davila“ Bucureºti, Facultatea de Medicinã Generalã, Spitalul Clinic Universitar de Urgenþã „Elias“

Bucureºti Clinica de Dermatologie / „Carol Davila“ Bucharest, Faculty of Medicine, University Emergency Hospital„Elias“

*** Spitalul de Boli Infecþioase ºi Tropicale „Dr. Victor Babeº“, Bucureºti / „Dr. Victor Babeº“ Infectious and TropicalDiseases Hospital, Bucharest.Bucharest Dermatology Clinic.

**** UMF „Gr. T. Popa“, Iaºi / UMF „Gr. T. Popa“, Iaºi.***** Facultatea de Medicinã Constanþa / Faculty of Medicine Constanþa.

****** Clinica Dermatologie II, Spitalul Clinic Colentina, Bucureºti / Dermatology Clinic II Clinical Hospital, Bucharest.******* Spitalul Clinic Colentina, Dermatologie II / Clinical Hospital Colentina, Dermatology II.

******** Centrul Medical al Serviciului de Telecomunicaþii Speciale / Medical Center of Special Telecommunications Service.********* Clinica Dermatologie, UMF Craiova / Dermatology Clinic, UMF Craiova.

********** UMF „Carol Davila“, Clinica I Dermatologie, Spitalul Colentina, Bucureºti / „Carol Davila“, Clinic of Dermatology,Hospital Colentina, Bucharest.

*********** UMF „Gr. T. Popa“, Iaºi, Clinica Dermato-Venerologie, Spitalul Clinic Universitar CF Iaºi / UMF „Gr. T. Popa“, Iasi,Clinical Dermatology, University Hospital CF Iaºi

************ Clinica Roderma, Iaºi / Roderma Clinic, Iaºi.************* U.M.F. “Carol Davila” Bucureºti, Facultatea de Medicinã, Disciplina Dermatologie / U.M.F. “Carol Davila” Bucharest,

Faculty of Medicine, Subject: Dermatology.

REFERATE GENERALEGENERAL REPORTS

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Introducere

SCOPUL TRATAMENTULUI BIOLOGICGrupul de lucru considerã ca principal scop

al tratamentului biologic în psoriazis creºtereacalitãþii vieþii pacientului în condiþiile menþineriieficacitãþii ºi siguranþei terapiei biologice. Înconsecinþã, orice schimbare a terapiei biologicetrebuie fãcutã numai de medicul curant cuconsimþãmântul informat al pacientului ºirespectarea normelor în vigoare.

În acest context, discuþia despre terapiilebiologice ºi biosimilare constituie un subiect deactualitate ºi de real interes în lumea medicalã.Acest articol îºi propune sã aducã în luminã ºi sãclarifice diverse aspecte legate de terapiabiologicã, incluzând procesul de producþie,aprobarea de cãtre autoritãþile competente,obþinerea indicaþiilor, stabilirea profilului desiguranþã ºi procesul de farmacovigilenþã.

Documentul în cauzã reprezintã opiniagrupului de lucru menþionat mai sus ºi estevalidat de comitetul executiv al SocietãþiiRomâne de Dermatologie.

1. Terapiile biologice originale ºibiosimilare: definiþii

Pentru a avea o înþelegere comunã a ter-menilor folosiþi în acest document, prezentãm încele ce urmeazã principalele definiþii utilizate decãtre organizaþiile internaþionale relevante.

Definiþii ale produselor biologiceWHO (World Health Organization) -

“Produsele biologice sunt definite ca substanþe deorigine biologicã, evaluate prin intermediultestelor biologice ºi utilizate în profilaxia, terapiasau diagnosticul afecþiunilor umane”1.

EMA (European Medicines Agency) -“Produsul biologic este o substanþã care esteprodusã sau extrasã dintr-o sursã biologicã ºi care

Introduction

PURPOSE OF BIOLOGICAL THERAPYThe Working Group considers that the main

goal of the biological therapy in psoriasis isimproving patient’s quality of life while main-taining the efficacy and safety of the biologicaltherapy.

Consequently, any change in the biologicaltherapy should be made only by the attendingphysician with the patient’s informed consentand in compliance with the applicableregulations.

In this context, the discussion on biologicaland biosimilar therapies is topical and of greatinterest in the medical world. This article aims tobring light on and clarify various aspects of thebiological therapy, including production process,approval by competent authorities, getting direc-tions, safety profiling and pharmacovigilanceprocess.

This document contains the opinion of theworking group mentioned above and is validatedby the Executive Committee of the RomanianSociety of Dermatology.

1. Original and biosimilar biologicaltherapies: definitions

To have a common understanding of theterms used in this document, please see belowthe main definitions used by the relevantinternational organizations.

Definitions of biological productsWHO (World Health Organization) -

„Biological products are defined as substances ofbiological origin, evaluated through biologicaltests and used in the prophylaxis, therapy ordiagnosis of human diseases.“1

EMA (European Medicines Agency) -„Biological product is a substance that is

Grupul de lucru îºi exprimã adeziunea la puntul devedere al EMA privind utilizarea medicamentelor ºi ainterschimbabilitãþii acestora susþinând cã nu este permisswitch între un medicament biosimilar ºi medicamentul dereferinþã.

Cuvinte cheie: terapie, biosimulare, psoriazis,declaraþii de consens.

The working group expresses its adherence to EMA’spoint of view on the use of drugs and their inter-changeability, stating that a switch is not allowed betweena biosimilar drug and its reference product.

Key-words: therapy, biosimulars, psoriasis,consensum statement.

Intrat în redacþie: 15.02.2017Acceptat: 7.03.2017

Received: 15.02.2017Accepted: 7.03.2017

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necesitã o multitudine de testãri fizico-chimico-biologice desfãºurate în timpul procesului deproducþie pentru a asigura controlul permanental calitãþii”2.

EMA (European Medicines Agency) -“Biosimilarele sunt versiuni structurale foartesimilare ale unui medicament biologic dejaautorizat (medicament de referinþã), similaritateafiind demonstratã în caracteristicile fizico-chimice, eficacitate ºi siguranþã, pe baza uneicomparaþii cuprinzãtoare”3,4.

Definiþiile de mai sus subliniazã complexitateaproduselor biologice

Existã o diferenþã majorã, care trebuiesubliniatã, între medicamentele convenþionaleobþinute prin sintezã chimicã ºi medicamentelebiologice originale sau biosimilare (în principalproteine) care sunt produse în organisme vii (liniicelulare). Odatã cu expirarea patentului pentruun medicament convenþional existã posibilitateareplicãrii cu exactitate a structurii sale chimice,ceea ce duce la apariþia medicamentului generic.În cazul produselor biologice, replicareastructurii acestora nu se poate realiza cuexactitate, datã fiind complexitatea structurii, aprocesului tehnologic ºi a exclusivitãþii linieicelulare primordiale (din care se extrage în finalproteina biologicã).

De aceea, produsul rezultat va fi „foartesimilar” din punct de vedere structural, dar nucomplet identic cu produsul biologic de referinþã.

Prin urmare, planul de dezvoltare amedicamentelor biosimilare pune accentul pestabilirea similaritãþii de structurã, nu abeneficiului clinic.

produced or extracted from a biological sourceand requires a lot of physical-chemical-biologicaltesting undertaken during the productionprocess to ensure a permanent quality control“2

EMA (European Medicines Agency) -„Biosimilars are very similar structural versions ofa biological medicine already authorized(reference drug), this similarity being proved bytheir physico-chemical characteristics, efficacy andsafety, based on a comprehensive comparison“3,4

The above definitions stress the complexity ofbiological products

There is a major difference, which needs to behighlighted, between conventional drugsobtained by chemical synthesis and bioproductsor biosimilars (mainly proteins) which areproduced in living organisms (cell lines). Uponexpiry of the patent for one conventional drug, itis possible to exactly replicate its chemicalstructure, which leads to a generic drug. Forbiological products, replicating their structurecannot be done accurately, given the complexityof the structure, technological process andexclusivity of the primordial cell line (wherefromthe biological protein is finally extracted).

Therefore, the resulting product will be„highly similar“ from a structural point of view,but not identical to the reference biologicalproduct.

Therefore, the development plan of biosimilarmedicines emphasizes the establishment ofstructural similarity, not of clinical benefit.

2. Variability of biological productsComparability and bio-similarity are two

distinct concepts.

Biosimilar

ReferenceProduct

Produsulde

Referinþã

Biosimilar Due to the inherent complexityand variability of bioproducts, abiosimilar can never be „identical“to its reference product5

Datoritã complexitãþii inerente ºivariabilitãþii biologicelor, unbiosimilar nu poate fi niciodatã„identic“ cu produsul sãu dereferinþã.5

Totuºi, niciun lot al oricãruiprodus biologic de referinþã nupoate fi „identic“ cu lotulprecedent.5

However, no batch of anyreference biological product canbe „identical“ to the previousbatch5

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2. Variabilitatea produselor biologice Comparabilitatea ºi biosimilaritatea repre-

zintã douã concepte distincte.Definirea termenilor privind VARIABILITATEA

PRODUSELOR BIOLOGICE.• În cadrul aceleiaºi Denumiri Comerciale (DC)

– COMPARABILITATEConceptul de comparabilitate se referã la

demonstrarea similaritãþii între loturi distincteale aceluiaºi medicament în contextul diverselorschimbãri apãrute în procesul de producþie post-autorizare.• În cadrul aceleiaºi Denumiri Comune

Internaþionale (DCI) – BIOSIMILARITATEConceptul de biosimilaritate reprezintã

termenul utilizat de cãtre autoritãþile dindomeniul medicamentului din UniuneaEuropeanã pentru a desemna gradul desimilaritate dintre un medicament biosimilar ºimedicamentul biologic de referinþã.

Autorizaþia de punere pe piaþã a unuimedicament biosimilar are la bazã o evaluareprin care se aratã cã solicitantul a demonstratsimilaritatea cu medicamentul de referinþã pecãile stabilite de cãtre Comitetul pentruMedicamente de Uz Uman (CHMP) sau de cãtreghidurile ºtiinþifice ale EMA referitoare lamedicamentele biosimilare.

Post-autorizare ºi un producãtor debiosimilare poate face modificãri în procesul deproducþie ºi în aceastã situaþie va urma o evaluarede comparabilitate (a propriului produs),conform ICHQ5E (Note for guidance onbiotechnological/biological products subject tochanges in their manufacturing process(CPMP/ICH/5721/03).

3. Extrapolarea indicaþiilor unui produsbiosimilar

Extrapolarea permite aprobarea unuibiosimilar pentru o indicaþie terapeuticã în carenu a fost evaluat prin propriile studii clinice, darpentru care produsul de referinþã este aprobat6.

Extrapolarea indicaþiilor unui Biosimilar înconformitate cu reglementãrile autoritãþilorcompetente (EMA7 si FDA8) necesitã obligatoriuevidenþe per ansamblu de biosimilaritate ºi ojustificare adecvatã, þinând cont de comorbidi-tãþile diferite ºi implicit de medicaþia conco-mitentã diferitã.

Defining the terms regarding the VARIABILITYOF BIOLOGICAL PRODUCTS.• Within the same TRADE NAME (TN)

–COMPARABILITYThe concept of comparability relates to

demonstrating the similarity between differentbatches of the same medicine in the context ofthe various changes occurring in the post-authorization production process.

• Within the same INTERNATIONAL NON-PROPRIETARY NAME (INN) - BIOSIM-ILARITY

The concept of bio-similarity is the term usedby authorities in the field of medicines in theEuropean Union to designate the degree ofsimilarity between a biosimilar and thebiological reference medicine. The marketingauthorization of a biosimilar medicine is basedon an assessment showing that the applicant hasdemonstrated similarity to the reference productin the ways established by the Committee forHuman Medicinal Products (CHMP) or by EMAscientific guidelines on biosimilar medicines.

Post-authorization, a manufacturer ofbiosimilars can also make changes in themanufacturing process and in this case anassessment of comparability (of his own product)will follow, in accordance with ICHQ5E (Note forguidance on biotechnological/biological productssubject to changes in their manufacturing process(CPMP/ICH/5721/03)).

3. Extrapolation of indications of abiosimilar product

Extrapolation allows for approval of abiosimilar for a therapeutic indication in which ithas not been evaluated by own clinical trials butfor which the reference product is approved.6

Extrapolation of indications of a Biosimilar inaccordance with the competent authorities(EMA7 and FDA8) requires mandatory biosimilaroverall records and an adequate justification,considering the different comorbidities andimplicitly the different concomitant medication.Differences between certain features of thebiosimilar product (glycosylation, purification,preparation form and storage conditions) and thereference product can impact the effectivenessand safety profile.9 Potentially, these changesmay have a different impact depending on thecondition for which the drug is used.

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Diferenþele între anumite caracteristici aleprodusului biosimilar (glicozilare, purificare,formã de condiþionare ºi condiþii de pãstrare) ºicele ale produsului de referinþã pot impactaeficacitatea ºi profilul de siguranþã9. Potenþial,aceste modificãri pot avea un impact diferit înfuncþie de boala pentru care este folositmedicamentul.

În prezent, existã un numãr limitat de studiiclinice pentru produsele biosimilare în psoriazis.De aici ºi preocuparea dermatologilor privindextrapolarea indicaþiilor pentru biosimilareavând în vedere diferenþele existente, atât în ceeace priveºte patogenia, cât ºi în ceea ce priveºtecomorbiditãþile.

4. ImunogenicitateaImunogenicitatea reprezintã procesul de

formare de anticorpi împotriva unui agent strãinsau a unui medicament10 ºi reflectã un rãspunsimun fiziologic. Toþi agenþii biologici pot induceun rãspuns imun nedorit11. Intensitatea formãriide anticorpi împotriva agenþilor biologicidepinde în principal de proprietãþile structuraleale medicamentului12. O consecinþã importantã aimunogenicitãþii poate fi modificarea farmaco-cineticii agenþilor biologici, conducând astfel laniveluri serice subterapeutice de medicament13.

Populaþii diferite de pacienþi pot avea unpotenþial diferit privind rãspunsul imunogenic14,de aceea alegerea populaþiei de studiu reprezintão preocupare cheie în evaluarea corectã aimunogenicitãþii.

Conform recomandãrilor EMA15 (EuropeanMedicines Agency) :- “Populaþia inclusã în studiu trebuie sã fie

reprezentativã pentru indicaþiile terapeuticeaprobate ale produsului de referinþã ºi sã fiesuficient de sensibilã pentru a detectapotenþialele diferenþe între biosimilar ºimedicamentul biologic de referinþã.”

- “Pentru medicamentele biologice cu indicaþiimultiple, imunogenicitatea poate prezentadiferenþe între indicaþii, iar absenþa evaluãriiîntr-o anume indicaþie a biosimilarului artrebui justificatã.”

Grupul de lucru considerã cã NU trebuiepermis SWITCH-ul între un medicament biologicde referinþã ºi medicamentul biosimilar SAU întreun medicament biosimilar ºi medicamentulbiologic de referinþã SAU între medicamentele

There are currently a limited number ofclinical trials for biosimilar products in psoriasis.Hence the dermatologists’ concern regardingextrapolation of indications for biosimilars giventhe existing differences in both the pathogenesisand the comorbidities.

4. Immunogenicity

Immunogenicity is the process of formationof antibodies against a foreign agent or a drug10

and reflects a physiological immune response.All biological agents can induce an undesiredimmune response.11 The intensity of theformation of antibodies against biological agentsmainly depends on the structural properties ofthe drug.12 An important consequence ofimmunogenicity can be the alteredpharmacokinetics of biological agents, leading tosub-therapeutic drug serum levels13.Different populations of patients may have adifferent potential concerning the immuno-genetic response14, therefore the choice of thestudy population is a key concern in the properassessment of immunogenicity.

According to EMA15 (European MedicinesAgency) recommendations:- “The population included in the study should

be representative for the approved therapeuticindications of the reference product andsufficiently sensitive to detect potentialdifferences between the biosimilar and thebiological reference medicine.”

- “For biological medicinal products withmultiple indications, immunogenicity maydiffer depending on the indication and theabsence of evaluation in a particular indicationof the biosimilar should be justified.”

The Working Group considers that aSWITCH between a reference biological medicineand the biosimilar medicine or between abiosimilar medicine and the biological referencemedicine OR between biosimilar medicines withthe same INN (International Non-ProprietaryName) should NOT be allowed. The mainargument is the increased risk of development ofanti-drug antibodies by highlighting differentepitopes. The opinion of the Working Group isthat further studies on immunogenicity ofbiosimilars are needed for a clear position on thissubject.

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biosimilare în cadrul aceluiaºi DCI (DenumireComunã Internaþionalã). Principalul argument esteriscul crescut de dezvoltare a anticorpilor anti-medicament prin evidenþierea unor epitopi diferiþi.

Opinia grupului de lucru este cã suntnecesare studii suplimentare privind imuno-genicitatea biosimilarelor, pentru a statuta opoziþie clarã asupra acestui subiect.

5. Interschimbabilitate, Schimbare (switch),Substituþie automatã

Conceptele de Interschimbabilitate, Schim-bare (switch) si Substituþie automatã sunt înru-dite ºi au fost importate de la medicamentelegenerice cu moleculã micã.

Interschimbabilitatea reprezintã practicaalternãrii între medicamente fãrã ca aceasta sãinducã un risc semnificativ de apariþie a unorrezultate clinice neprevãzute pentru sãnãtateapacienþilor.1,2

Schimbare (switch) reprezintã decizia medi-cului de a trece de pe un medicament pe altul, deobicei pentru a optimiza tratamentul sau pentru areduce la minimum reacþiile adverse.2,3

Conform recomandãrilor EMA15 (EuropeanMedicines Agency) :- “Populaþia inclusã în studiu trebuie sã fie

reprezentativã pentru indicaþiile terapeuticeaprobate ale produsului de referinþã ºi sã fiesuficient de sensibilã pentru a detectapotenþialele diferenþe între biosimilar ºimedicamentul biologic de referinþã.”

- “Pentru medicamentele biologice cu indicaþiimultiple, imunogenicitatea poate prezentadiferenþe între indicaþii, iar absenþa evaluãriiîntr-o anume indicaþie a biosimilarului artrebui justificatã.”

Grupul de lucru considerã cã NU trebuiepermis SWITCH-ul între un medicament biologicde referinþã ºi medicamentul biosimilar SAU întreun medicament biosimilar ºi medicamentulbiologic de referinþã SAU între medicamentelebiosimilare în cadrul aceluiaºi DCI (DenumireComunã Internaþionalã). Principalul argument esteriscul crescut de dezvoltare a anticorpilor anti-medicament prin evidenþierea unor epitopi diferiþi.

Opinia grupului de lucru este cã suntnecesare studii suplimentare privind imunogeni-citatea biosimilarelor, pentru a statuta o poziþieclarã asupra acestui subiect.

5. Interchangeability, Change (Switch),Automatic Substitution

The concepts of Interchangeability, Change(Switch) and Automatic Substitution are relatedand have been imported from small-moleculegenerics.Interchangeability is the practice ofalternating between drugs without inducing asignificant risk of occurrence of unforeseenclinical results for patients’ health.1,2

Change (Switch) is the doctor’s decision topass from a drug to another, usually to optimizetreatment or to minimize side adverse.2,3

According to EMA15 (European MedicinesAgency) recommendations:- “The population included in the study should

be representative for the approved therapeuticindications of the reference product andsufficiently sensitive to detect potentialdifferences between the biosimilar and thebiological reference medicine.”

- “For biological medicinal products withmultiple indications, immunogenicity maydiffer depending on the indication and theabsence of evaluation in a particular indicationof the biosimilar should be justified.”

The Working Group considers that aSWITCH between a reference biological medicineand the biosimilar medicine or between abiosimilar medicine and the biological referencemedicine OR between biosimilar medicines withthe same INN (International Non-ProprietaryName) should NOT be allowed. The mainargument is the increased risk of development ofanti-drug antibodies by highlighting differentepitopes.The opinion of the Working Group isthat further studies on immunogenicity ofbiosimilars are needed for a clear position on thissubject.

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Bibliografie / Bibliography1. World Health Organization. WHO Expert Committee on Biological Standardization. 2011.2. EMA. Q&A: Similar biological products: Definition of biological medicinal products. 2001.3. EMA Website. Glossary. . Accessed October 17, 2013.4. Weise M et al. Nat Biotechnol. 2011;29(8):690-693.5. Schneider CK. Ann Rheum Dis 2013;72:315–318. 6. Dörner et al. Ann Rheum Dis 2013;72:322–328. 7. European Medicines Agency. Guideline on similar biological medicinal products containing monoclonal antibodies—non-

clinical and clinical issues. EMA/CHMP/BMWP/403543/2010. 30 May 2012. 8. US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a

reference product [Draft]. February 2012. 9. Schellekens et al. NDT Pls 2009;2:i27-i36.10. Schellekens H. Clin Ther. 2002;24:1720-1740. 11. Wolbink GJ, et al. Curr Opin Rheumatol. 2009;21:211-215. 12. Emi Aikawa N, et al. Clin Rev Allergy Immunol. 2010;38:82-89. 13. NechanskyA, KircheisR. Expert OpinDrug Discov .2010;5:1067–1079. 14. FDA guidance. FDA Scientific Considerations in demonstrating biosimilarity to a reference product [Draft]. February

2012. 15. EMA. CHMP/BMWP/42832/2005 Rev 1 [Draft] 03 June 2013.

Conflict de interese Conflict of interestNEDECLARATE NONE DECLARED