BiosimilarsBiosimilars

Prof. Dr. János BorvendégProf. Dr. János BorvendégCHMP CHMP membermember

HungaryHungary

Do we have a market for biosimilar?Do we have a market for biosimilar?

The market is driven by two factorsThe market is driven by two factors::

bby unmet clinical needs (diseases y unmet clinical needs (diseases

unmanageable with conventional unmanageable with conventional

therapeutics)therapeutics)

bby a premium pricey a premium price

The biopharmaceutical market is very The biopharmaceutical market is very attractiveattractive

10 % - 15 % of the world pharmaceutical 10 % - 15 % of the world pharmaceutical

marketmarket

growth between 2004-2010:growth between 2004-2010:

3,4 % year for total market3,4 % year for total market

11 % year for biopharmaceuticals11 % year for biopharmaceuticals

biosimilar market in EU + US 16,4 billion $biosimilar market in EU + US 16,4 billion $

by 2011by 2011

The The most important patent expirationsmost important patent expirations::imigluceraseimiglucerasehuman insulinhuman insulinsomatropinsomatropininterferon alfainterferon alfainterferon betainterferon betaerythropoietinerythropoietinfilgrastimfilgrastimtPAtPAIL-2IL-2sterptokinasesterptokinase

Sales in 2006 and predicted sales in 2010 for Sales in 2006 and predicted sales in 2010 for six leading biosimsix leading biosimiilars in US lars in US $$

global salesglobal sales growthgrowth proportion in proportion in US marketUS market

predicted sales predicted sales 20102010

ErythropoietinErythropoietin 13 billion13 billion 7 %7 % 69 %69 % * 701 million* 701 million

Human growth Human growth hormonehormone

1,9 billion1,9 billion 2 %2 % 33 %33 % ** 442 million** 442 million

Recombinant Recombinant human insulinhuman insulin

8,0 billion8,0 billion ** 138 million** 138 million

Interferon alfaInterferon alfa 2,3 billion2,3 billion 6 %6 % 35 %35 % ** 188 million** 188 million

Interferon betaInterferon beta 3,7 billion3,7 billion 55 %55 % * 131 million* 131 million

G-CSFG-CSF 5,6 billion5,6 billion 15 %15 % 63 %63 % ** 605 million** 605 million

* EU markets only* EU markets only

** US + major EU markets** US + major EU markets

Recent regulatory issues in biosimilarity assessment Recent regulatory issues in biosimilarity assessment and acceptance by the Regulatory Agenciesand acceptance by the Regulatory Agencies

USA:USA:

„„Promoting Innovation and Access to Life-Promoting Innovation and Access to Life-Saving Medicine Act” HR. 1427Saving Medicine Act” HR. 1427(11.03. 2009)(11.03. 2009)Mr. Waxman’s billMr. Waxman’s bill

„„Pathways for Biosimilars Act” (draft)Pathways for Biosimilars Act” (draft)Mrs. Eshoo bill (competing approach)Mrs. Eshoo bill (competing approach)

Extracts from the Act H.R. 1427Extracts from the Act H.R. 1427 definition (biological, reference product)definition (biological, reference product) regulations of Biosimilars and Interchangeable regulations of Biosimilars and Interchangeable

biological productsbiological products submission of abbreviated biological product submission of abbreviated biological product

applicationapplication approval of biosimilar or Interchangeable biological approval of biosimilar or Interchangeable biological

productsproducts determinations on interchangeabilitydeterminations on interchangeability market exclusivity for the original and market exclusivity for the original and

biosimilar/interchangeable productsbiosimilar/interchangeable products-*--*-

standard requirements for biosimilarity and for standard requirements for biosimilarity and for interchangeability have to be established by the FDA interchangeability have to be established by the FDA (within 2 years of passage of the bill).(within 2 years of passage of the bill).

Recent regulatory issues in biosimilarity assessment and acceptance Recent regulatory issues in biosimilarity assessment and acceptance by the Regulatory Agenciesby the Regulatory Agencies

EU/EMEAEU/EMEA

Several guidelines onSeveral guidelines on Comparability exercises (non-clinical/clinical)Comparability exercises (non-clinical/clinical)

EMEA/CHMP 49348/2005EMEA/CHMP 49348/2005EMA/CHMP 42832/2005EMA/CHMP 42832/2005

PK of therapeutic proteinsPK of therapeutic proteinsEMEA/CHMP 89249/2004EMEA/CHMP 89249/2004

Immunogenicity assessmentImmunogenicity assessmentEMEA/CHMP/BWP/24511/2005EMEA/CHMP/BWP/24511/2005

Quality issuesQuality issuesEMEA/CHMP/BWP/3204EMEA/CHMP/BWP/3204-EMEA/CHMP/BWP/49348/2005-EMEA/CHMP/BWP/49348/2005

Validation of bioanalytical Validation of bioanalytical mmethodethodeeEMEA/CHMP/EWP/531305/2008 (concept paper)EMEA/CHMP/EWP/531305/2008 (concept paper)

Development, production, characterisation and specification for mAB Development, production, characterisation and specification for mAB and related productsand related productsEMEA/CHMP/BWP/157653/2007EMEA/CHMP/BWP/157653/2007

Basic principles of the EMEA regulation on Basic principles of the EMEA regulation on biosimilar products (BP)biosimilar products (BP)

BP have different levels of complexityBP have different levels of complexity The regulatory requirements are guided (on case by The regulatory requirements are guided (on case by

case basis) by thecase basis) by the- extent of the physicochemical/biological - extent of the physicochemical/biological characterisation of the product, characterisation of the product,- nature of possible changes in the quality/structure of - nature of possible changes in the quality/structure of the biological product due to the changes in the the biological product due to the changes in the manufacturing process (and their expected outcomes) manufacturing process (and their expected outcomes)- clinical/regulatory experiences with the particular - clinical/regulatory experiences with the particular class of the product in question class of the product in question

The „traditional” bioequivalence (PK/PD) studies can not The „traditional” bioequivalence (PK/PD) studies can not be applied with the same relevancebe applied with the same relevance

What is a Biosimilar Product?What is a Biosimilar Product?

Biosimilar, or similar biological medicinal product Biosimilar, or similar biological medicinal product is „a new biological medicinal product, similar is „a new biological medicinal product, similar to licensed reference medicinal product” to licensed reference medicinal product” in: in: - quality- quality - efficacy- efficacy - safety- safety

Biological medicinal products:Biological medicinal products:contain biotechnology derived products ascontain biotechnology derived products asactive substanceactive substance

Biosimilar and reference biological medicines are Biosimilar and reference biological medicines are similar but not identicalsimilar but not identical

Biopharmaceuticals are different from Biopharmaceuticals are different from traditional medicines:traditional medicines:

Complex manufacturing processComplex manufacturing process

High molecular weightHigh molecular weight

Complex 3-D structureComplex 3-D structure

Difficult to characterizeDifficult to characterize

Stability problemsStability problems

Immunogenicity Immunogenicity

Factors which may change the structure of the Factors which may change the structure of the proteins during the manufacturing process (even proteins during the manufacturing process (even under strictly controlled condition).under strictly controlled condition).

Chemically:Chemically:ooxidation, deamidation, xidation, deamidation, disulfide shufflingdisulfide shufflingracemisationracemisation

Physically:Physically:unfoldingunfoldingmisfoldingmisfoldingaggregationaggregationprecipitationprecipitationfragmentationfragmentation

Quality considerationsQuality considerations

„„full” Quality dossier is requiredfull” Quality dossier is required

„„State of Art” analytical methodsState of Art” analytical methods

(physicochemical plus bioanalytical)(physicochemical plus bioanalytical)

Additional elementsAdditional elements

- comparability exercise- comparability exercise

- focusing on possible differences in:- focusing on possible differences in:

manufacturing processmanufacturing process

minor structural diff.minor structural diff.

impuritiesimpurities

Non-clinical considerationsNon-clinical considerations

Comparative studies (similarity and Comparative studies (similarity and

differences at several doses leveldifferences at several doses level))

in vitro: in vitro: receptor bindingreceptor binding

cell based assayscell based assays

in vivo: in vivo: PK/PDPK/PD

Toxicity:Toxicity: spec. tox.spec. tox.

rutin tox.?rutin tox.?

How to design clinical studies?How to design clinical studies?

Clinical studies with biosimilar productsClinical studies with biosimilar products

Requirements depend onRequirements depend on- type/properties of the biological product- type/properties of the biological product- extent of the physicochemical/biological - extent of the physicochemical/biological characterisationcharacterisation- non-clinical analysis- non-clinical analysis- therapeutic indication- therapeutic indication- clinical experiences of the reference product- clinical experiences of the reference product

Stepwise procedure:Stepwise procedure:- PK- PK- P- PDD- Therapeutic equivalence studies- Therapeutic equivalence studies

Pharmacokinetic (Pharmacokinetic (PPK) considerations:K) considerations: The requirements for PK studies are the same as for The requirements for PK studies are the same as for

conventional product conventional product (single dose/steady state studies)(single dose/steady state studies)

Specific problems of bio-analysisSpecific problems of bio-analysis- validation of the analytical assay- validation of the analytical assay (specificity, accuracy, precision, limit of detection) (specificity, accuracy, precision, limit of detection)- methodological problems- methodological problems drug assay (interference with endogen substances) drug assay (interference with endogen substances) antibody assay (presence of the active substance antibody assay (presence of the active substance in the plasmain the plasma))

Specific problems in PK clinical studiesSpecific problems in PK clinical studies- great variability (inter/intra subject)- great variability (inter/intra subject)- immunogenicity (antibody formation)- immunogenicity (antibody formation) change in PK parameters change in PK parameters

Pharmacodynamic (PD) considerations:Pharmacodynamic (PD) considerations:

Availability of PD markers/surrogate Availability of PD markers/surrogate biomarkersbiomarkers

Sensitivity to changes in activity?Sensitivity to changes in activity? Do they signal clinical endpoints?Do they signal clinical endpoints? Is there quantitative relationship between Is there quantitative relationship between

the surrogate and clinical endpoint?the surrogate and clinical endpoint? Is there coIs there corrrelation between the PK an PD relation between the PK an PD

values?values? Are they validated?Are they validated?

Equivalence efficacy/safety clinical trialsEquivalence efficacy/safety clinical trials General recommendationsGeneral recommendations Are these clinical trials really needed?Are these clinical trials really needed?It depends on:It depends on:- mechanism of action of the biological product mechanism of action of the biological product

(disease specific?)(disease specific?)- indication (target organ)indication (target organ)- PK propertiesPK properties- availability of surrogate markersavailability of surrogate markers- safety profile andsafety profile and- immonogenicity of the productimmonogenicity of the product- sensitivity of the clinical studysensitivity of the clinical study- clinical experiences with the reference productclinical experiences with the reference product

Individualized regulatory requirements for Individualized regulatory requirements for clinical comparative studiesclinical comparative studies

Recombinant human insulin (rh Insulin)Recombinant human insulin (rh Insulin)PK: single dose, cross-over (in patients PK: single dose, cross-over (in patients with type II diabetes) with type II diabetes)

AUC, Cmax, tmax, t/2AUC, Cmax, tmax, t/2PD: double blind, cross-over (ePD: double blind, cross-over (euuglycaemic clamp)glycaemic clamp)Efficacy: waived if the biosimilarity is justified by Efficacy: waived if the biosimilarity is justified by PK/PD dataPK/PD dataSafety: 6 months (Pre-approval) studySafety: 6 months (Pre-approval) study

12 months (Post-marketing) study 12 months (Post-marketing) study commitmentcommitmentPhV.P: PhV.P: - allergic reactions- allergic reactions

- compare the daily dose of previous- compare the daily dose of previous and of the new insulin and of the new insulin,, needed by the needed by the

patients patients

Individualized regulatory requirements for Individualized regulatory requirements for clinical comparative studiesclinical comparative studies (cont.)(cont.)

Human Somatropin (rSTH)Human Somatropin (rSTH)PK: single dose, cross-over comparative s.c.PK: single dose, cross-over comparative s.c. in in healthy healthy volunteers (AUC, Cmax, tmax, t/2) volunteers (AUC, Cmax, tmax, t/2)PD: biomarkers PD: biomarkers IGF-1IGF-1 IGF BP-3IGF BP-3Efficacy: Efficacy: - comparative, double blind, parallel groups in - comparative, double blind, parallel groups in hypophyser dwarfshypophyser dwarfs- endpoints: growth in cm/year, SD score- endpoints: growth in cm/year, SD score- duration: 6-12 months- duration: 6-12 monthsSafety: immunotoxicity (12 months)Safety: immunotoxicity (12 months) IGF-1, IGF BP-3, insulin, plasma glucoseIGF-1, IGF BP-3, insulin, plasma glucosePhV.P: PhV.P: - diabetogen effect- diabetogen effect

- in- inccidency of malignancyidency of malignancy- anti rh GH antibodies- anti rh GH antibodies

Individualized regulatory requirements for Individualized regulatory requirements for clinical comparative studiesclinical comparative studies (cont.)(cont.)

rG-CSFrG-CSFPK: single dose, cross-over comparative PK: single dose, cross-over comparative (s.c./i.v.) (s.c./i.v.) (AUC, Cmax, tmax, t/2) (AUC, Cmax, tmax, t/2)PD: absolute neutrophil count. (CD34)PD: absolute neutrophil count. (CD34)Efficacy: (indications)Efficacy: (indications)- mitigation of neutropenia- mitigation of neutropenia(at chemo th./myeloablative th)(at chemo th./myeloablative th)- mobilisation of progenitor cells- mobilisation of progenitor cells- congenit./idiopathic neutropenia- congenit./idiopathic neutropeniaSafety: - 6 months comparative trialSafety: - 6 months comparative trial - immunogenicity- immunogenicityPhV.P/Risk Management ProgramPhV.P/Risk Management Program

Individualized regulatory requirements for Individualized regulatory requirements for clinical comparative studiesclinical comparative studies (cont.)(cont.)

Interferon alfaInterferon alfaPK: single dose, cross-over s.c./i.v.PK: single dose, cross-over s.c./i.v. healthy volunteers healthy volunteersPD: - PD: - -2 microglobulin-2 microglobulin - neopterin - neopterin

- se 2’, 5’ –oligoadenylate synthetase activity - se 2’, 5’ –oligoadenylate synthetase activityEfficacy: Efficacy: - randomised, parallel group, comparative- randomised, parallel group, comparative - treatment naive patients with HCV - treatment naive patients with HCV 48 weeks 48 weeksEndpoints:Endpoints: - undetectable levels of HCV RNA (by quantitative - undetectable levels of HCV RNA (by quantitative PCR)PCR) - co-primary end- co-primary endppoint: 2-10 oint: 2-10 loglog decrease in viral load decrease in viral loadSafety: - flu-like illness, alopecia, myalgia, lSafety: - flu-like illness, alopecia, myalgia, leeucopenia, ucopenia, anaemia, thro anaemia, thrommbocytopenia bocytopenia = R= Ref. Prep.ef. Prep.

- immunogenicity/neutralising capacity- immunogenicity/neutralising capacityExtrapolation: „if the mechanism of actions known to Extrapolation: „if the mechanism of actions known to be the same condition” be the same condition”

Individualized regulatory requirements for Individualized regulatory requirements for clinical comparative studiesclinical comparative studies (cont.)(cont.)

Low Molecular Weight-HeparinsLow Molecular Weight-HeparinsPK: noPK: nott applicable applicablePD: single dose, randomized, cross-overPD: single dose, randomized, cross-over healthy volunteers healthy volunteers ssurrogate markers: anti F Xaurrogate markers: anti F Xa anti F 11a anti F 11a activityactivity

TFPI TFPIEfficacy: Efficacy: - randomised, double blind, parallel group- randomised, double blind, parallel group th. th. eequivalence studyquivalence study - prevention of venous/arterial thrombolism- prevention of venous/arterial thrombolism treatment /VTE, DVT, PE)treatment /VTE, DVT, PE) - patients with major orthopedic surgery- patients with major orthopedic surgery ultra sonographyultra sonography renographyrenography

deathdeathSafety: - major bleedingSafety: - major bleeding - heparin induced thrombocytopenia - heparin induced thrombocytopeniaPhV.P/Risk Management ProgramPhV.P/Risk Management Program

Individualized regulatory requirements for clinical Individualized regulatory requirements for clinical comparative studiescomparative studies (cont.)(cont.)

Recombinant ErRecombinant ErytythropoietinshropoietinsPK: single dose, cross-over, comparative (s.c./i.v.)PK: single dose, cross-over, comparative (s.c./i.v.)PD: comparative, multiple dose (4 weeks) PD: comparative, multiple dose (4 weeks) dose ascending dose ascending

endpoint: change in Hgb endpoint: change in HgbEfficacy: Efficacy: - comparative, randomized, parallel groups, double - comparative, randomized, parallel groups, double blindblind ▫▫ correction phase (s.c.) correction phase (s.c.) ▫ maintenance phase (i.v.)▫ maintenance phase (i.v.) - target population (anaemia due to chronic renal - target population (anaemia due to chronic renal faliure)faliure) - 6 month- 6 month - endpoints: Hgb level – in - endpoints: Hgb level – in correctioncorrection/maintenance /maintenance phasephase the reacting patients i the reacting patients inn % % epo epoetinetin dosage dosage transfusion requirements transfusion requirementsSafety: imSafety: immmunounotoxtoxicity (12 months, comparative)icity (12 months, comparative) Ph.V.P. + Risk Management Program Ph.V.P. + Risk Management ProgramExtension to other indication: allowedExtension to other indication: allowed

Is it simple to make a biosimilar?Is it simple to make a biosimilar?

Leading biosimilar playersLeading biosimilar players::

Teva Pharmaceuticals – Lonza (Basel)Teva Pharmaceuticals – Lonza (Basel)

Biopartners (Barr, SBiopartners (Barr, Swwitzerland) – Biotonitzerland) – Bioton rrGGH, Alpheon (interferon alfa)H, Alpheon (interferon alfa)

Sandoz (generic aSandoz (generic arrm of Novartis (Basel) m of Novartis (Basel) MerMercck k CCoo.. Merck Bio Ventures Merck Bio Ventures

Omnitrope (rGH)Omnitrope (rGH)Binocrit (Binocrit (EEpoetin poetin aalfa Hexal)lfa Hexal)filgfilgrrastimastim

Insmed (Insmed (RRichmond VA) rG-CSFichmond VA) rG-CSFpegylated rG-CSFpegylated rG-CSF

Smaller biosimilar – focused companiesSmaller biosimilar – focused companies

CangeCangenene (Winnipeg) (Winnipeg) Hospira (Lake Forest)Hospira (Lake Forest)

Phage (BiotecPhage (Biotechhnology, San-Diego)nology, San-Diego)

Gene Medix (Offaly, Ireland)Gene Medix (Offaly, Ireland)

Emerging biosimilar developersEmerging biosimilar developers Dragon Pharmaceutical (Vancouver)Dragon Pharmaceutical (Vancouver)

ShantShantaa Biotech (New Delhi) Biotech (New Delhi)

BBharat Biotech (harat Biotech (HHyderabyderabaad, India)d, India)

Hurdles in the faster growth of biosimilar Hurdles in the faster growth of biosimilar marketmarket

Biosimilars are specific productsBiosimilars are specific products

Regulations for marketing approval are much Regulations for marketing approval are much

stricter than those for conventional genericsstricter than those for conventional generics

The required capital investment and cost of The required capital investment and cost of

manufacturing are much higher for biosimilars manufacturing are much higher for biosimilars

and the probability of successful lauand the probability of successful laucch is h is

lower than those for chemical-based generics lower than those for chemical-based generics

Hurdles in the faster growth of biosimilar Hurdles in the faster growth of biosimilar marketmarket (cont.)(cont.)

Post-approval safety monitoring is Post-approval safety monitoring is compulsorycompulsory

Manufacturers of innovator/branded products Manufacturers of innovator/branded products are likely use sophisticated defensive tactics are likely use sophisticated defensive tactics (improved delivery devices, improving the PK (improved delivery devices, improving the PK properties of the original products etc.)properties of the original products etc.)

Physicians are reluctant to switch to Physicians are reluctant to switch to biosimilar productsbiosimilar products

Relatively small price differentRelatively small price differentcece (20-25 % (20-25 % discount optimum) reduces the incentive to discount optimum) reduces the incentive to switch.switch.

The significance of biosimilar products The significance of biosimilar products (BP) can not be ignored(BP) can not be ignored

tthe majority of BP-s is of very important he majority of BP-s is of very important medicine (including th. medicine (including th. ffor cancers, genetic or cancers, genetic diseases)diseases)

tthe price of the innovator BP-s is extremely he price of the innovator BP-s is extremely highhigh

tto curb the healthcare spending and to o curb the healthcare spending and to promote the access to life-saving medicines promote the access to life-saving medicines are in the interest of the whole societyare in the interest of the whole society

Opportunities in the Biosimilar Market in the futureOpportunities in the Biosimilar Market in the future

Key factors:Key factors: Capital investmentCapital investment

- financial strength- financial strength- combination of generic and branded business- combination of generic and branded business- licensing, collaborations, and mergers- licensing, collaborations, and mergers

DevelopmentDevelopmentexpertise in: expertise in: - manufacturing proteins- manufacturing proteins - sophisticate analytical methods - sophisticate analytical methods - - clinical studies (comparative PK/PD/Th studies)clinical studies (comparative PK/PD/Th studies)

Marketing expertise in sales, promotionMarketing expertise in sales, promotion,, safety safety monitoringmonitoring

-*--*- Rational and flexible regulation of marketing Rational and flexible regulation of marketing

authorisationauthorisation. . Simplified guidelinesSimplified guidelines.. Suitable price policy / price competitionSuitable price policy / price competition The financial policy / capability of the Social Security The financial policy / capability of the Social Security

systemsystem

„„Outlook”Outlook”

I am optimistic….I am optimistic….aand you?nd you?