Global Trends on

pharmacovigilance and

interchangeability of

Reference Products and

Biosimilars

Dr Valderilio Feijó Azevedo, MD, PhD, MBA

Associate Professor of Rheumatology of Universidade Federal do Paraná

ASAS

GRAPPA executive commitee

General Coordinator of the Latin American Forum on Biosimilars

Conflicts of Interest

• Adjunct Professor of rheumatology at the Federal University of Paraná,

Brazil

• R & D Director for new biopharmaceutical product development at

Edumed biotech

• Clinical investigational fees from Pfizer, Roche, Janssen, Bristol, Abbott,

Medimmune, Boehringer, GSK, UCB, Sanofi

• Financial support to participate in meetings and give conferences to

Pfizer, Roche, MSD, BMS, Merck Serono, Janssen and Novartis

Presentation

• What is interchangeability?

• Why interchangeability shouldn´t be just a matter of physician/patient decision

• Switching: medical and non-medical switching

• Overview scenario for interchangeability of biosimilars

• Concerns on switching

• Why interchangeability has to be connected with a robust pharmacovigilance system?

• Overall impact of these data to clinical practice, including their impact on policy related to stable patients

• Currently Switching data on Biosimilars

• Conclusions

Objectives

Sir William Osler

“Medicine is a Science

of Uncertainty and an

Art of Probability”

Biosimilars

Biosimilars

Regulatory developments

Decrease health care costs

Public Health Care

(Safety)

State Policy

Financial Investiments

Market opportunities

Biosimilars interchangeability

• Interchangeability of a biosimilar/reference product is a property

granted to two pharmaceutic products that permits both to be switched

between one and other without generating any significant clinical

difference in terms of efficacy and safety.

• The question is who is going to make this decision?

Definitions

Automatic substitution:

Practice of dispensing one medicine instead of another equivalent and interchangeable

medicine at the pharmacy level without consulting the prescriber

Interchangeability:

A regulatory designation for a medicine (such as a biosimilar): an interchangeable biological

product, in addition to meeting the biosimilarity standard, is expected to produce the same

clinical result as the reference product in any given patient

Switching:

The decision to exchange one medicine for another with the same therapeutic intent in

patients who are undergoing treatment

1. Rubin, et al. ECCO 2015, Barcelona, P354; 2. Gibofsky, et al. AMCP 2015, San Diego, Poster; 3. Liu Y, et al. ISPOR 2015, Philadelphia,

PHS26; 4. Morgan, et al. Open Medicine 2009;3:131‒9; 5. Declerck. GaBi J 2012;1:13–6; 6. Van Assche, et al. Gut 2012;61:229‒34.

Non-medical Switching (NMS)

NMS, non-medical switching.

What is NMS? • Switching of biologics among patients with well-tolerated,

adequate therapy1–3

What motivates

NMS? • Potential for cost-savings and/or procurement policies1−4

• Patient preference1,2

What types of

NMS occur? • Across different agents from the same class2,6

• From a reference product to its biosimilar or vice versa

Who decides interchangeability?

Biosimilars – Curb your Enthusiasm

• 81 peer reviewed studies. Based on past experience with generic small-

molecules in US and Biosimilars in Europe Union, the investigators

estimated savings from biosimilars would range from 10% to 50% within 10

years after introduction. Additional assumptions: grown rate of 10%

annualy for originator products, the share of biologic subject to biosimilar

competition ranging from 10% in the first year to 20% in the 10th year.

• Potential direct saving in US of U$ 44.2 billion year.

• Us regulatory may hamper potential savings.

• No interchangeability biosimilar Market will only be Worth U$ 4.6 billion by

2019.

• Penetrance with interchangeability 35%-70& without less than 10%

Yang YT, et al. JAMA Oncol. 2017

WHO EMA FDA Health Canada Austrália

Não há uma posição final, apenas reconhece a

importância desse tópico.

EMA não avalia se um produto é

intercambiável. Deve ser discutido

com o médico e farmacêutico.

Cada país membro trata destes temas individualmente.

Determina se o produto é

biossimilar e se é intercambiável.

Há uma lista “Purple Book” que identifica

se o produto é biossimilar (B) ou

biossimilar e intercambiável (I).

Não apoia a substituição automática e recomenda a

decisão médica desde que bem

informada.

TGA aprova se o produto é

biossimilar. Pharmaceutical

Benefits Advisory Committee (PBAC)

decide se o produto poderá ser

substituído pelo farmacêutico com

base em dados clínicos.

Interchangeability – Global regulatory status

1. Macdonald JC, et al. mAbs 2015;7:653–61.

Switching & Interchangeability

In Europe, no regulatory definition on interchangeability

but generally understood as relating to switching

• Member states set individual policies on switching,

automatic substitution and other prescribing practices

In Europe and the US

Interchangeability

means different

things in US

and EU!

FDA definition of interchangeability1

• Requires demonstration of achieving same clinical effect in

every patient

• However no scientific standard for achieving interchangeability

• Once granted by FDA and when state laws permit allows

pharmacy level substitution without the intervention of a

prescriber

Interchangeability – Anvisa

Drug Revolution? Are We Prepared to Prescribe Biosimilars?

1. Azevedo VF. Bras J Rheumatol 2010;50(3):221–24.

Familiarity With Biosimilars

LATIN AMERICA

35%

53%

12%

Haven't heard of them or could not define them

Familiar, have a basic understanding of them

Very familiar, I have a complete understanding of

them

Awareness of Different Classes of Biologics

LATIN AMERICA

“Are you aware of the difference between biologics, biosimilars and non-comparable biologics? ” (N=399)

49% 51%

Yes No

More Data Builds Confidence

More data showing that safe use, including safe switching, does not result in differences in efficacy, adverse effects or discontinuation rates will increase physician (and patient) confidence

18

1. FDA Biologics Price Competition and Innovation Act of 2009, HR 3590:686-703;

2. 56th Consultation on INN for Pharmaceutical Substances, Geneva: WHO, 2013, INN working document 13.335.

Switching Between reference products and Biosimilars

“A biosimilar… must be evaluated against 1 reference product”1

Reference product “A” Biosimilar “B”

Biosimilar “C”, “D”

B

C

A

1. EMA. Benepali™ EPAR;p57; 2. FDA Advisory Committee Briefing Document GP2015 (INN: Etanercept) BLA. June 6 2016. Table 24

3. O’Dell J. Abstract 16-1800. Presented at the The European League Against Rheumatism Annual Congress, 8-11 June, 2016, London, UK.

Three Etanercept Biosimilars

Test Samsung Benepali (SB4)1 Sandoz Erelzi (GP2015)2* Coherus (CHS0214)3

SB4 Enbrel GP2015 Enbrel CHS0214 Enbrel

ADA + (Week 8) 2 (0.7%) 38 (12.8%) 0 5 (1.9%) x x

ADA + (Week 24) 2 (0.7%) 39 (13.2%) 0 5 (1.9%) 1.3% 4.7%

ADA + (Week 52) 3 (1.0%) 39 (13.2%) 0 5 (1.9%) x x

nAb + (Week 8) 0 1 0 0 x x

nAb + (Week 24) 0 1 0 0 0 0

nAb + (Week 52) 0 1 0 0 x x

Immunogenicity

ADA, anti-drug antibody; nAb,

neutralising antibody.

*Data for study 302 in patients with psoriasis

X means not stated

1. Singh JA, et al. Arthritis Rheumatol 2016;68:1–26; 2. Smolen J, et al. Ann Rheum Dis 2014;73:492–509;

3. Dignass A, et al. J Crohns Colitis 2010;4:28–62.

Medically Relevant Switching

• Patients treated with biologic

therapy, who have an

inadequate response or an

intolerable AE, should be

switched to a different biologic

agent for clinical reasons1–3

Evidence-based Recommendation

Algorithm based on 2016 EULAR recommendations on RA management: Phase II

aTNFi (ADA, CZP, ETN, GOL, IFX), ABA, IL-6 inhibitors, or RTX; IL-6 inhibitors and tsDMARDs may have advantages in patients who cannot use csDMARDs as comedication bCurrent practice is to start with a bDMARD (+ MTX or another csDMARD) cThe treatment target is clinical remission, according to ACR–EULAR definition, or at least LDA; the target should be reached after 6 months, treatment should be altered if inadequate improvement after 3 months dThe most frequently used combination is MTX, SSZ, and hydroxychloroquine eDose reduction or interval increase can safely be done with all bDMARDs with little risk of flares Smolen JS, et al. Ann Rheum Dis 2017;0:1–18

Dose reduction/interval

increase in sustained remissione

Phase II Prognostically unfavorable

factors present Prognostically unfavorable

factors absent

Change to or add a second csDMARD:

LEF, SSZ, MTX alone, or in combinationd

(ideally with addition of GCs as in Phase I)

No

Achieve improvement at 3 months and target at

6 monthsc

such as RF/ACPA, especially at high levels; high disease activity, early

joint damage; failure of ~2 sDMARDs

Achieve improvement at 3 months

and target at 6 monthsc

Failure Phase II: go to Phase III

No Continue Yes

Failure for lack of efficacy and/or toxicity in Phase I

Add a bDMARDa (current practice)

or a JAKib

bDMARD may include an originator or its biosimilar

Non medical switching : Medical societies

“A BSR desaconselha a mudança sumária de todos os pacientes que atualmente recebem um produto de referência que é eficaz e bem tolerado para um

biossimilar. A decisão de mudar deve ser feita caso a caso e até que dados adicionais sejam disponibilizados para corroborar a mudança segura; fortes salvaguardas são

necessárias para assegurar que os pacientes que responderam bem a um medicamento existente não sejam mudados por motivos não clínicos”1

• 1. British Society for Rheumatology Position Statement on Biosimilar Medicines, Feb 2015, http://www.rheumatology.org.uk/about_bsr/press_releases/bsr_supports_the_use_of_biolsimilars_but_recommends_measures_to_monitor_safety.aspx. Last accessed May 19, 2016; 2. ACR Position Statement on Biosimilars, Mar 2015, http://www.rheumatology.org/About-Us/Newsroom/Press-Releases/ID/33/ACR-Releases-New-Position-Statement-on-Biosimilars-Encourages-Strict-Oversight-Scientific-Study-Physician-Involvement. Last accessed May 19, 2016; 3. Azevedo VF, Meirelles Ede S, Kochen Jde A, et al. Recommendations on the use of biosimilars by the Brazilian Society of Rheumatology, Brazilian Society of Dermatology, Brazilian Federation of Gastroenterology and Brazilian Study Group on Inflammatory Bowel Disease--Focus on clinical evaluation of monoclonal antibodies and fusion proteins used in the treatment of autoimmune diseases. Autoimmun Rev. 2015;14(9):769-73.

“O ACR acredita que existe muito desconhecimento sobre biossimilares para presumir que a mudança repetida será uma prática segura”2

“As 4 instituições fortemente apoiam a introdução de biossimilares no mercado brasileiro(...) Os especialistas não permitem a substituição automática, porque

ela acontece sem consentimento médico”3

Position Statements Medical Societies are Influencing Doctors’ Prescriptions

1. Moots R, Azevedo VF, Mysler E, Scheinberg M, Dorner T. ACR 2016.

Several Biosimilars are Attempting to Answer the Issue of Switching through Clinical trials

Trials Blind. Arms Switch phase

• CT-P13 vs infliximab PLANETRA (n=617) and PLANETAS (n=257)

• SB4 vs etanercept (n=498) • CHS-0214 vs etanercept (RA=620, PsO=496) • CT-P10 vs rituximab • CT-P13 (n=302) • GP2015 vs etanercept (EQUIRA) (RA=366)

OL extension

Two–One

Switch to biosimilar open-label extension (single arm)

• SB2 vs infliximab (n=584) • SB5 vs adalimumab (n=490)

DB Two–Three

Switch to 3-arm study; biosimilar arm continues, originator arm splits into originator and biosimilar arm

• DWP422 vs etanercept (n=38) • HD203 vs etanercept (n=294) • LBEC0101 vs etanercept (n=372)

DB Two Cross-over switch (two arms) (with washout period between cross-over)

• TuNEX vs etanercept (n=98) OL Two Cross-over switch (two arms) (with washout period between cross-over)

• GP2015 vs etanercept (EGALITY) (PSO=531) DB Two–Four

Transition to four-arm study: each arm splits into two arms – one continues and one undergoes repeated switching

• CT-P13 vs infliximab NOR-SWITCH (n=500), SIMILAR (n=330) • M923 vs adalimumab

DB One–Two

Split into two arm (one continues, one switches)

• CT-P13 vs infliximab (BIO-SWITCH, n=200)

OL One–Two

Split into two arm (one continues, one switches)

Key Considerations for Patients in Switching

1. Loss of efficacy after switching

2. Secondary failure due to ADAs

3. Other acute reactions (ISR, infusional AEs, etc.)

4. Infections profile different from reference product

5. Any difference detected in safety profile from biosimilars compared

with reference product

What are the Safety Concerns with Biosimilars?

ADA, anti-drug antibody; AE, adverse

event; ISR, injection-site reaction.

• Ten Years of biosimilars in Europe: development and Evolution of the regulatory pathways .Schiestl M. et al. Drug Des Devel Ther. 2017

• Biologicals and biosimilars: safety issues in Europe. Portela MDCC, et al. Expert Opin Biol Ther. 2017

- 802 pacientes com tratamento estável com IFX (m=6,8 anos) CT=P13

- Atividade de doença similar após 3 meses

- Retenção ajustada: 83,4% (levemente menor do que controles históricos com IFX)

Immunogenicity rates: anti-infliximab and anti-adalimumab

Diferent indications

Disease % pacientes with anti-infliximab antibodies

%of patients with anti adalimumab antibodies

References

RA 8 a 51% 12 a 37%

Crohn´s Disease 14 a 61% 0,04 a 17%

JIA NI 16 Lovell Dj et al. 2008

AS 29% 31% De Vries MK et al. 2007, 2009

PsA NI 18% Van Kuijk AW et al., 2010

Pso NI 45%

Wolbink GJ, et al., 2006

Bendtzen K, et al., 2006

Van de Putte LBA et al. 2004

Vermeire S et al, 2007 Baert F et al. , 2003

Hannauer SB et al. , 2002, 2006 Sandborn WJ et al. , 2007

Lecluse LL et al.,2010

Mok CC et al. Expert Opin Biol Ther. 2016;16(2):201-11

The NOR-SWITCH STUDY

Kvien T et al. UEGW LB15, Vienna, 2016

Late-breaking abstracts

LB01 SIX WEEKS OF SOFOSBUVIR/LEDIPASVIR TREATM ENT OFACUTE HEPATITIS C VIRUS GENOTYPE 1 M ONOINFECTION:FINAL RESULTS OF THE THE GERM AN HEPNET ACUTE HCV IVSTUDY

K . Deterding1, C.D. Spinner2, E. Schott3, T.M . Welzel4, G. Gerken5,H. K linker6, U. Spengler7, J. Wiegand8, J. Schulze zur Wiesch9, A. Pathil10,M . Cornberg1, A. Umgelter2, C. Zollner3, S. Zeuzem4, A. Papkalla1, K . Weber1,S. Hardtke1, H. von der Leyen1, A . K och1, D. von Witzendorff1, M . M anns1,H. Wedemeyer1

1Hannover/DE, 2M unich/DE, 3Berlin/DE, 4Frankfurt/DE, 5Essen/DE, 6Wurzburg/DE, 7Bonn/DE, 8Leipzig/DE, 9Hamburg/DE, 10Heidelberg/DE

Contact E-mail Address: Deterding.K atja@mh-hannover.deIntroduction: Early treatment of acute hepatitis C virus (HCV) infection withinterferon alfa monotherapy is highly effective but is associated with frequentunfavorable side effects. There is no fully published study yet exploring thesafety, efficacy and required treatment duration of interferon-free treatment ofacute hepatitis C virus monoinfection. Preliminary reports suggested that ledi-pasvir/sofosbuvir therapy is effective in acute hepatitis C but relapses werereported in HIV-coinfected patients after 6 weeks of treatment.Aims & M ethods: The German HepNet Acute HCV IV Study was designed as asingle-arm, prospective multicenter pilot study to evaluate the efficacy and safetyof treatment with sofosbuvir plus ledipasvir (SOF/LDV) for 6 weeks withoutribavirin in patients with acute genotype 1 HCV monoinfection. We herereport the final 24 weeks’ post-treatment results.Results: Twenty patients were included by 10 centers (60% male, mean age46 12 years; 11 patients HCV genotype 1a, 9 patients genotype 1b). Themain risk factors for HCV infection were sexual transmission (n¼11) and med-ical procedures/needle stick injuries (n¼5). M edian alanine aminotransferase(ALT) and median bilirubin levels before start of antiviral treatment were 225U/l (range 32–2716) and 13.6mmol/l (range 5.13–111), respectively. ALT levelsrapidly declined during therapy and values normalized already by treatmentweeks 2 in nine patients and by week 4 in 17 patients. HCV RNA was undetect-able by the Roche COBASÕ AmpliPrep/COBASÕ TaqM anÕ HCV Test v2.0 byweeks 2, 4 and 6 in eight, 13, and 20 patients, respectively. SVR-12 was 100% and19 patients have completed FU-week 24 and all remained HCV-RNA negative.One patient was lost to follow-up at week 24 post treatment.Conclusion: Treatment for 6 weeks with LDV/SOF was well tolerated and highlyeffective in HCV genotype 1 monoinfected patients with acute hepatitis C.Virological response was durable after therapy for at least 24 weeks. A rapidimprovement in biochemical disease activity was observed during therapy. Short-duration treatment of acute hepatitis C could prevent the spread of HCV in high-risk populations and may be cost-saving as compared with treatment of chronichepatitis C.Disclosure of Interest: K atja Deterding: Lecturer fees and travel grants fromGilead, M SD/M erck and AbbVieEckart Schott: Lecture fees/consulting fees, travel support: Gilead, BM S, M SD/M erck, AbbVie, JanssenTania Welzel: Lecture fees/consulting fees, travel support: AbbVie, BM S, Gilead,Novartis JanssenHartwig K linker: Lecture fees/consulting fees, travel support: AbbVie, BM S,Gilead, Janssen, M SD; Advisory board: AbbVie, BM S, Gilead, Hexal,Janssen; M SD Grants: AbbVie, BM S, Gilead, Janssen, M SD, Arrowhead,NovartisJulian Schulze zur Wiesch: Lecture fees/consulting fees, travel support: Gilead,AbbVieM arkus Cornberg: Lecture/consulting fees, travel support: AbbVie, BM S,Boehringer, Biogen Idec, Falk, Gilead, Janssen, M SD/M erck, RocheDiagnostics, Roche Pharma, SiemensAndreas Umgelter: Lecture fees/consulting fees, travel support: GileadCaroline Zollner: Lecture fees/consulting fees, travel support: BMS, Gilead, JanssenStefan Zeuzem: Lecture fees/consulting fees, travel support: AbbVie, BM S,Gilead, Janssen, M SD/M erck Grants: GileadM ichael M anns: Lecture fees/consulting fees, travel support/grants: Roche,BM S, Gilead, Boehringer, Novartis, M SD/M erck, Janssen, GlaxoSmithK line,Biotest, Achillion, AbbVieHeiner Wedemeyer: Lecture fees/consulting fees, travel support/grants: BM S,AbbVie, Abbott, Gilead, Novartis, Roche, M SD/M erck, Janssen, Transgene,Roche Diagnostics, Boehringer, Eiger, M yr GmbH.

LB02 THE REAL-WORLD ROM ANIAN EXPERIENCE OFTREATING CHRONIC HEPATITIS C, GENOTYPE 1 B PATIENTSWITH COM PENSATED CIRRHOSIS WITH PARITAPREVIR/OM BITASVIR/RITONAVIR, DASABUVIR WITH RIBAVIRIN: ANATIONAL COHORT STUDY*

C.M . Preda, C.P. Popescu, C. Baicus, M . M anuc, R. Voiosu, E. Ceausu,L. Fulger, A. Nisanian, C.S. Pop, A. OproiuBucharest/RO

Contact E-mail Address: preda_monicaa@yahoo.com

Introduction: Direct antiviral agents (DAA) showed very good results in terms ofefficacy and safety in clinical trials,1 but real-life data are still needed in order toconfirm this profile.2

Aims & M ethods: In Romania, through a governamental programme, approx.5000 patients with virus C compensated liver cirrhosis will receive reimbursedDAA with Paritaprevir/Ombitasvir/ritonavir, Dasabuvir with Ribavirin for 12weeks during 2015–2016. We analysed a national prospective cohort enrolling654 patients who started the therapy in December 2015–January 2016. Allpatients had genotype 1b. The only key inclusion criteria was Child-Pugh score4 6. Only serious adverse events leading to discontinuation of therapy werereported. Data were obtained from the National Health Insurance House.Efficacy was assessed by the percentage of patients achieving SVR (HCV RNAundetectable) 12 weeks post-treatment (SVR12). Ordinal and scale variables withnon-normal distribution were summarized as median (min, max), and comparedby Mann–Whitney U test, while categorical variables were summarized asnumber (%) and compared by Fisher exact test.Results: Two patients were lost to follow-up because of adverse events probablynot related to therapy, eight stopped the treatment because of hepatic decom-pensation (1.2%), one patient stopped because of severe arrythmia (drug–druginteraction involved). This cohort was 46% females, mean age 58.16 years (35–79), 67% pre-treated with Peg-Interferonþ Ribavirin, 70% associated NASH,72% with severe necro-inflammatory activity (severity score 3- Fibromax), 30%with co-morbidities, 11.8% with Child Pugh A 6 points, 10 with virus B co-infection (all of them with HBV-DNA viral load below 20IU/ml). The meanM ELD (model for end stage liver disease) score was 6.15 3.01 (0.5–20). SVRwas reported in 641/644 (99.53%), 3/644 relapsed. Due to the small sample ofpatients it was not possible to identify predictive factors for viral response. Liverdecompensation was statistically associated with higher BM I (body mass index)(p¼0.029), higher bilirubin (p¼0.001), higher M ELD score (p¼0.001) andlower platelet count (p¼0.005).Conclusion: Paritaprevir/Ombitasvir/ritonavir, Dasabuvir with Ribavirin provedto be highly efficient in our population of cirrhotics with a 99.53% SVR. Seriousadverse events related to therapy were reported in 9/641 (1.4%), most of themliver decompensation (1.2%), for which we identified the following risk factors:higher IM C, higher bilirubin, higher M ELD score and lower platelet count.*These data are the property of the Romanian government.

References

1. Dore GJ, Conway B and Luo Y, et al. Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in gen-otype 1 HCV patients: The M ALACHITE-I/I I trials. J Hepatol 2016; 64(1):19–28.

2. Zuckerman E, Ashkenasi E, K ovalev Y, et al. The real-world Israeli experi-ence of treating chronic hepatitis C, genotype 1 patients with advancedfibrosis with Paritaprevir/Ritonavir/Ombitasvir, Dasabuvir with or withoutribavirin: A large multi-center cohort. PS007. International L iver Congress(ILC), the Annual M eeting of the EASL, Barcelona, April 2016.

Disclosure of Interest: All authors have declared no conflicts of interest.

LB03 M ULTI-PORT VERSUS SINGLE-PORTCHOLECYSTECTOM Y: RESULTS OF A M ULTICENTRERANDOM ISED CONTROLLED TRIAL (M USIC TRIAL)

A. Arezzo1, R. Passera1, A . Bullano1, Y. M intz2, A . K EDAR2, L . Boni3,E. Cassinotti3, R. Rosati4, U. Fumagalli5, M . Sorrentino6, M . Brizzolari6, N. DiLorenzo7, A.L. Gaspari7, D. Andreone8, E. De Stefani8, G. Navarra9,S. Lazzara9, M . Degiuli1, K . Shishin10, I . K hatkov10, I . K azakov10,R. Schrittwieser11, T. Carus12, A. Corradi12, G. Sitzman13, A . Lacy14,S. Uranues15, A. Szold16, M .A. Bonino1, M . M orino1

1Torino/IT, 2Jerusalem/IL, 3Varese/IT, 4M ilano/IT, 5Rozzano ( mi) /IT,6Latisana/IT, 7Roma/IT, 8Orbassano/IT, 9M essina/IT, 10M oscow/RU, 11Bruck AnDer M ur/AT, 12Bremen/DE, 13Tuebingen/DE, 14Barcelona/ES, 15Graz/AT, 16TelAviv/IL

Contact E-mail Address: alberto.arezzo@mac.comIntroduction: Single port laparoscopic surgery as an alternative to standardlaparoscopy in patients undergoing cholecystectomy for benign disease has notyet been accepted as standard procedure. The aim of the M Ulti-port versusSIngle-port Cholecystectomy (M USIC) trial was to compare single access(SPC) with standard laparoscopy (M PC) in terms of morbidity.Aims & M ethods: A non-inferiority phase 3 trial was undertaken at 20 centresand hospitals in six countries. Patients requiring cholecystectomy were randomlyassigned to either SPC or M PC, in each centre. Primary outcome was overallmorbidity within 60 days from surgery. Analysis was by intention to treat. Thestudy was registered with ClinicalTrials.gov, number NCT01104727.

United European Gastroenterology Journal2016, Vol. 4(6) 800–811! Author(s) 2016Reprints and permissions:sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2050640616678364ueg.sagepub.com

Jørgensen KK et al. www.thelancet.com, 2017

Pacientes estáveis, pelo menos, por

6 meses com REMICADE

Remsima

Remicade

Todos com REMICADE

Randomização 1:1

500 pacientes Piora da doença

Semana 52

Piora da doença Semana 52

Seguimento Semana 78

Seguimento Semana 78

Endpoint 10

52 semanas

• Assumindo piora da resposta de 30% em 52 semanas • Margem de Não-inferioridade: ± 15%

The NOR-SWITCH STUDY Study design

Jørgensen KK et al. www.thelancet.com Published online May 11, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30068-5

NOR-SWITCH: Diagnostics and sample size

Size n =481 2,3

Psoríase 35

Doença de Crohn 155

Colite Ulcerativa 93

30 Artrite Psoriásica

Espondiloartrites 91

Artrite Reumatoide 78

Diagnóstic1,2 INX (n=241) CT-P13

(n=240)

Crohn 78 (32.4%) 77 (32.1%)

UC 47 (19.5%) 46 (19.2%)

spondyloarthritis 45 (18.7%) 46 (19.2%)

RA 39 (16.2%) 38 (15.8%)

PsA 14 (5.8%) 16 (6.7%)

Pso 18 (7.5%) 17 (7.1%)

1. Jorgensen KK et al Lancet 2017, online first

* Piora da doença

• RCU: aumento do p-Mayo ≥ 3 e p-Mayo ≥ 5

• DC: aumento do HBI ≥ 4 e HBI ≥ 7

• AR/PsA: aumento do DAS28 de ≥1,2 desde a randomização a DAS ≥ 3,2

• AS/EsA: aumento do ASDAS de ≥1,1 e ASDAS ≥ 2,1

• Psoríase: aumento do PASI de ≥3 desde a randomização ao mínimo de PASI ≥ 5

Remicade N = 202

Remsima N = 206

Diferença (IC 95%)

PIORA DA DOENÇA * 53 (26,2%) 61 (29,6%) -4,4 (12,7 a 3,9)

Endpoint Primário Piora da doença em 52 semanas

Jørgensen KK et al. www.thelancet.com, 2017

Piora da doença

Remicade N = 202

Remsima N = 206

Diferença (IC 95%)

Doença de CROHN 14 (21,2%) 23 (36,5%) -14,3% (-29,3 a -0,7%)

Retocolite Ulcerativa 3 (9,1%) 5 (11,9%) -2,6% (-15,2 a 10,%)

Espondiloartrite 17 (39,5%) 14 (33,3%) 6,3% (-14,5 a 27,2%)

Artrire Reumatóide 11 (36,7%) 9 (30%) 4,5% (-20,3 a 29,3%)

Artrite psoriática 7 (53,8%) 8 (61,5%) -8,7% (45,5 a 28,1%)

Psoríase 1 (5,9%) 2 (12,5%) -6,7% (-26,7 a 13,2%)

TOTAL 53 (26,2%) 61 (29,6%) -4,4% (-12,7 a 3,9%)

Jørgensen KK et al. www.thelancet.com, 2017

• What are de MABs and Fusion proteins swiching data generated from pivotal studies, extension studies and real life data?

Is there a reason for concern or is it just hype? – A systematic literature review of the clinical consequences of switching from

originator biologics to biosimilars. InotaiA, et al. Expert Opin Biol Ther. 26:1-12. 2017

• Systematic literature review on Pubmed to identify

consequences of switching from RP to biosimilars

• 153 papers. 58 (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) included.

• Preventing patients on biologic medicines from switching RP to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient acess.

Product Manufacturer/ Commercial partner

Reference Development status

Countries using the drug

Reditux Dr. Reddy Rituximab Marketed Bolivia, Chile, India and Peru

Kikuzubam Probiomed Rituximab Marketed, withdrawn in Mexico

Bolivia, Chile, Mexico and Perú

Etanar Shanghai CP Goujian Pharmaceutical Co

Etanercept Marketed Colombia, Panama and Ecuador

Yisaipu Shanghai CP Goujian Pharmaceutical Co

Etanercept Marketed China

Infinitam Probiomed Etanercept Marketed Mexico

Etart Shanghai CP Goujian Pharmaceutical Co/Landsteiner

Etanercept Approved, not yet marketed

Mexico

1. Moctezuma JF, et al. EULAR 2013;Abstract THU0208. 1. Castañeda-Hernández, Azevedo V F et al. Joint Bone Spine. 2014 Jun 20.

INTENDED COPIES AVAILABLE IN LATIN AMERICA1

Pharmacovigilance

Post-marketing surveillance is critical1,2

1. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. 2. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010. 3. MRHA. Pharmacovigilance - how we monitor the safety of medicines. Available at: http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/Pharmacovigilance/index.htm [Accessed December 2013].

EMA, European Medicines Agency; FDA, Food and Drug Administration; RCT, randomized controlled trial.

Pharmacovigilance: Follows far greater numbers of patients treated for much longer duration than RCTs, allowing the detection of rarer safety signals

Approval

RCTs: Small patient numbers mean potential risks may not be detected prior to approval

A risk management plan is required by FDA and EMA guidelines, which may need to include post-marketing observational studies, inclusion of the biosimilar in biologic registries and/or Phase IV comparative studies1,2

Figure created from 3

Ensuring Biosimilar Safety and Efficacy

What are the Key Points of a Good Pharmacovigilance System?

• At PANDRH’s Seventh Conference in 2013, results of a survey conducted by PAHO of at least two countries in each sub-region of Latin America demonstrated that more than half had not incorporated WHO guidelines at all, while 39 percent used only parts of the document.At the same PANDRH meeting, the World Health Organization (WHO) presented results of a survey of 15 drug regulatory agencies in Latin America demonstrating substantial differences in the approach to clinical considerations in the regulation of biotherapeutic products.

Pan American Health Organization (PAHO) (2013). WHO Survey on Biotherapeutic Products (focus on clinical issues). Presentation (Dr. Ivana Knezevic) at VII Conference of the Pan American Network for Drug Regulatory Harmonization. September 5-7, 2013, Ottawa, Canada. Accessed November 27, 2013. Available at: http://www.paho.org/hq/ index.php?option=com_docman&task=doc_download&gid=22904&Itemid=270&lang=en.

1. Azevedo VF, et al. GaBi Journal 2014 June 17 [Published online before print].

1. Azevedo VF, et al. GaBi Journal 2014 June 17 [Published online before print].

Recommendations

1. There is an urgent need for enhanced training of regulatory authorities on how to evaluate biosimilars

2. Region-wide working group should be established under the auspices of PAHO, comprised of representatives from regulatory authorities from various Latin American countries with expertise in biosimilars, to share their regulatory experience and plans related to biosimilars

3. Each country in Latin America should establish its own working group to assist regulatory authorities in their efforts to develop and introduce biosimilars into their respective countries

4. A dedicated portion on the PRAIS website (PAHO’s Regional Platform on Access and Innovation for Health Technologies) should be devoted to promote discussion on biosimilars. Such topics as ongoing studies, recent approvals and issues of concern would be the focus and would foster transparency

The Panel’s Perspectives on Current Status Led to the Following…

1. Azevedo VF, et al. GaBi Journal 2014 June 17 [Published online before print].

Recommendations

5. Countries in Latin America must enhance their efforts to improve

pharmacovigilance to include training more regulatory staff, more

public and professional awareness on the importance of reporting

adverse events and better systems to capture and analyse data.

Regulatory authorities should also establish a process whereby the

traceability of an adverse event to a biosimilar can be determined

6. Products previously approved as ‘intended copy’ drugs should be

evaluated according to regulations specific to biosimilars. It cannot be

assumed that a previously approved biopharmaceutical is actually a

biosimilar, regardless of current clinical experience

The Panel’s Perspectives on Current Status Led to the Following…

Conclusion

• Interchangeability is a property of two pharmaceutical products. All medical decisions must be done under the knowledge of the data on this property.

• To leave to doctors and patients this decision implies that both always have the appropriate knowledge to decide which molecule have or not this property, which of course, is not true.

• How to accept pharmaceutical products have such a property?Interchangeability data may be generated by pivotal trials, extension studies, real-life data(registries)

• Must be granted by a case-by-case evaluation.

• Interchangeability must be close linked to a robust pharmacovigillance system.

• Markets where automatic substitutions are authorized, interchangeability is rarely regulated. On the contrary, markets where automatic substitution is possible but not common, interchangeability tends to be highly regulated.

Muchas gracias!