1. Does Interchangeability Really Matters for
Biosimilars?
Gilberto Castañeda-Hernández
Departamento de Farmacología
Centro de Investigación y de Estudios Avanzados
del Instituto Politécnico Nacional
México, D.F.
2. Biosimilars are not generics because:
1.The innovator’s patent has not yet expired.
2.The route of administration is different.
3.The active molecule is not identical to that of the innovator.
4.The excipients are not the same with regard to the innovator.
Question 1
Correct answer: Number 3
3. Hypothesis tests, such as the Student t test, ANOVA, Chi Square,
etc. are no adequate for biosimilarity because:
1. The p value must be lower than 0.01.
2. It is not possible to detect a significant difference when few
subjects are included in the study.
3. The mathematical procedure is to complicated.
4. Non parametrical tests must be used.
Question 2
Correct answer: Number 2
4. An intended copy is:
1. A generic version of a biotherapeutic product.
2. A non-innovator biologic which has not fully demonstrated
biosimilarity.
3. A non-innovator biologic which is interchangeable with the
innovator.
4. A biologic product which being a different molecule with regard to
the innovator can be substituted.
Question 3
Correct answer: Number 2
5. An example of a interchangeability study for a biosimilar is:
1. A pharmacokinetic bioequivalence study.
2. A clinical comparative study.
3. The Framingham study.
4. The Norswitch study.
Correct answer: Number 4
Question 4
6. Statement of Possible Conflicts of Interest
• I am a Senior Investigator at the Center for Research and Advanced Studies
of the National Polytechnic Institute
in Mexico
• I have given lectures and participated in studies sponsored by: Abbott,
AbbVie, Actelion, Amgen, Astra-Zeneca, Bayer, Boehringer-Ingelheim;
Concordia, Lilly, Liomont, Medix, Merck-Serono, MSD, Novartis, Pfizer,
Roche, Sanofi, Sandoz, Senosiain, Silanes, Sophia, UCB
• I am not on the payroll or possess shares of any of these companies
7. http://www.biosimilarspipeline.com/
Humira 30
Remicade 17
Epoetin alfa 85
Neupogen 59
Neulasta 24
Enbrel 31
Rituxan 50
Herceptin 38
Lantus 10
Avastin 25
Insulin and Analogs 51
Interferons (alfa) 60
Interferons (beta) 27
Somatropins 34
Cancer indications 418
mAbs, mAb fragments 261
Some Polpular Targeted Reference Products.
No . Of biosimilars by reference product.
9. Innovator MAB/Cept DNA constructs: Genes
Design of Biosimilar MABs/Cepts by
Reverse Engineering
McCamish & Woollett. mAbs 3: 209-217, 2011
10. Transfection, Transcription, Translation
Adapted from: CHMP, Committee for Medicinal Products for Human Use Sources. Public Assessment Report. Remsima.
Procedure No. EMEA/H/C/002576/0000 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf:.
11. Protein macrostructures which could be adopted from the protein-synthesis to final 3D functional structure, L. King, J.; Protein Folding. American Association for the advancement of science. 1990. Washington pp 157-169.
Berger et al.Protein Glycosylation and its impact on Biotechnology. In Adv Biochem Engin/Biotechnol 127: 165-185, 2012.
Post-Transcription Processes:
Glycosylation, Folding and Affinity
13. Antigen Binding and ADCC
(Antibody Dependent Cellular Toxicity
Tracey D, et al. Pharmacol Ther 2008; 117:244–279; Vos ACW, et al. Inflamm Bowel Dis 2012;18:401–408; Vos ACW, et al. Gastroenterology 2011;140:221–230
14. EXPERT COMMITTEE ON BIOLOGICAL
STANDARDIZATION
Geneva, 19 to 23 October 2009
1. Introduction…………………………………………….…… 3
2. Aim…………… ……………………………………………... 4
3. Scope………………………………………………………… 5
4. Glossary……………………………………………………... 5
5. Scientific consideration………………………………….… 8
6. Key principles for the licensing of SBPs………...…… 10
7. Reference biotherapeutic product……………..………… 11
8. Quality………………………………………………………. 13
9. Non-clinical evaluation………………………………..….…22
10. Clinical evaluation………………………………………… ..26
11. Pharmacovigilance………………..……………………….. 38
12. Prescribing information and label…………..…………… 39
13. Roles and responsibilities of NRAs……………………… 39
Authors and Acknowledgements………………………...… 41
References…………………………………………………… 44
Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)
15. Approved Biosimilars (2016)
1. CT-P13 (Remsima®). Infliximab. Celltrion, South Korea. Approvad by EMA.
2. SB4 (Benepali®). Etanercept. Samsung-Bioepis. South Korea. Approved by EMA.
3. GP2015. Etanercept. Sandoz. Austria/Germany/Switzerland. Approved by FDA.
• What was the information submitted by this products to obtain authorization?
16. Physicochemical Characterization
MAbs. 2014;6(5):1163-77. doi:10.4161/mabs.32221.
Physicochemical characterization of Remsima.
Jung SK1, Lee KH, Jeon JW. Lee JW, Kwon BO, Kim YJ, Bae JS, Kim DI, Lee SY, Chang SJ.
MAbs. 2016 Aug-Sep;8(6):1136-55. doi:10.1080/19420862.2016.1193659.Epub 2016 May 31.
Evaluation of the structural, physicochemical, and biological
characteristics of SB4, a biosimilar of etanercept.
Cho IH1, Lee N1, Song D1, Jung SY1, Bou-Assaf G2, Sosic Z2, Zhang W2, Lyubarskaya Y2
Expert Opin Biol Ther. 2016 Oct;16(10):1185-95. doi:10.1080/14712598.2016.1217329. Epub 2016 Aug 16.
Characterization and non-clinical assessment of the proposed
etanercept biosimilar GP2015 with originator etanercept (Enbrel(®)).
Hofmann HP1, Kronthaler U1, Fritsch C2, Grau R, Müller SO3, Mayer R4, Seidi A5, Da Silva A1.
20. SB4 and Enbrel®: MoA Related Bioassays
Bioassays assessed the similarity of BenepaliTM and Enbrel® by analysing the relative binding potency of
BenepaliTM or Enbrel® to TNF‐α or lymphotoxin-alpha 3 (LT‐α3), along with a TNF‐α Neutralisation Cell
Based Assay
* The similarity range was set by statistical analysis based on the tolerance interval with the given set of
available data points.
DS, drug substance; DP, drug product; LT‐α, lymphotoxin‐alpha; MoA, mechanism of action; PVR, Process
validation run. Sources: BenepaliTM EPAR;p19,Table 1.
Cho et al. mAbs, DOI: 10.1080/19420862.2016.1193659
24. Remsima®: PK in patients with
Ankylosing Spondilitis
Park et al. Ann Rheum Dis. 2013 Oct;72(10):1605-12.
25. A randomized phase l pharmacokinetic study
comparing SB4 and etanercept reference
product (Enbrel®) in healthy subjects
British Journal of Clinical Pharmacology: Volume 82: pages 64-73, 2 MAY 2016 DOI: 10.1111/bcp.12929
http://onlinelibrary.wiley.com/doi/10.1111/bcp.12929/full#bcp12929-fig-0003
26. GP2015: PK in Healthy Volunterrs
• Mean serum concentration-time profiles were comparable between GP2015 and
etanercept originator
Afonso M et al. Poster at EULAR 2016; THU0145.
Mean serum concentration-time profile
28. Clinical Study Design
One well-designed study is better than multiple
poorly-designed assays
• Choose a suitable patient population. Inter-patient variability as low as possible
• Purpose: Show biosimilarity (comparison)
• Two Groups: Innovator vs Biosimilar
• Adequate primary endpoint
• Sufficient study length to be clinically relevant
ADEQUATE STATISTICAL ANALYSIS
• No hypothesis testing (Student t test, ANOVA)
• Demonstrate equivalence or, at least, non-inferiority
Dörner T et al. Ann Rheum Dis. 2013;72:322–328; Park et al. Ann Rheum Dis. 2013;
72:1605–1612; Yoo DH et al. Ann Rheum Dis. 2013;72:1613–1620.
29. What is a sensitive population?
Castañeda-Hernández, González-Ramírez, Kay & Scheinberg. RMD Open 2015;1e:000010. doi:10.1136-2014-000010
Placebo Treatment Placebo Treatment
R
B
R
NB
B
NB
Effect R: Reference product
B: Biosimilar
NB: Non-biosimilar
Insensitive Population Sensitive Population
Can extrapolate
Cannot extrapolate
31. Sensitive Population: Oncology
Neoadjuvant breast cancer treatment
as a sensitive setting for
trastuzumab biosimilar development
and estrapolation
Christian Jackisch*,1, Frank A Scappaticci2, Dminik
Heinzmann3, Fabio Bisordi3, Thomas Schreitmüller3, Gunter
von Minckwitz4 & Javier Cortés5
Future Oncol, 2015 Jan;11(1):61-71. doi 10.2217/fon.14.187
32. Limitations of Hypothesis Testing
• Failure to achieve statistical significance (p > 0.05) in a test designed for looking for
differences is not evidence of equivalence.
Castañeda-Hernández, González-Ramírez, Kay & Scheinberg. RMD Open 2015;1e:000010. doi:10.1136-2014-000010
N small
S large
Numberofsubjects
Parameter value
33. Equivalence Testing
• A and B are the efficacy parameter values of the innovator and biosimilar.
• Ideal A=B, i.e. A/B = 1. This is almost impossible.
• Thus, an equivalence range is chosen.
• An anti-TNFα agent, A (innovator) yields an effect 30% higher than placebo. Then,
the equivalence range for A/B can be 15%. A log-transformation is performed.
• The hypothesis to demonstrate is: 0.85 < A/B < 1.18
• Results expressed as A/B ± 95% C.I. The 95% C.I. must be within equivalence
range.
Castañeda-Hernández, González-Ramírez, Kay & Scheinberg. RMD Open 2015;1e:000010. doi:10.1136-2014-000010
34. To be or not to be (equivalent)
Castañeda-Hernández, González-Ramírez, Kay & Scheinberg. RMD Open 2015;1e:000010. doi:10.1136-2014-000010
Higher equivalence
Limit (1.18)
Lower equivalence
Limit (0.85)
Non-equivalent
Equivalent
95% confidence
interval
A/B 1
35. Yoo et al. Ann Rheum Dis 2013;72:1613-1620
CT-P13 response rates at week 24
(ACR20 primary endpoint)
36. SB4 response rates at week 24
(ACR20 primary endpoint)
Emery P, et al. Ann Rheum Dis. 2015
37. GP2015 Phase III study of GP2015
vs. etanercept in PsO (EGALITY)
PASI 75 primary Endpoint
• PASI 75 at Week 12 was the primary endpoint to assess equivalence
• Primary endpoint was achieved because the 95% CI of the PASI 75 response rate
difference fell within the pre-specified margin (-18%, 18%)
Griffiths CEM, Thaci D, Gerdes S, et al. Oral presentation. PSO Congress, Paris, France, 7 July 2016.
73.4% 75.7%
-2.3% (-9.85, 5.30)
73.4% 75.7%
39. Indication extrapolation
Adapted from: 1. FDA Draft Guidances – Scientific Considerations in Demonstrating Biosimilarity to a Reference Protein Product (Feb 2012) – US Guidance;
2. EMA: CHMP Guideline On Similar Biological Medicinal Products Containing Biotechnology-derived Proteins As Active Substance: Non-clinical And Clinical Issues (22 February 2006); 3. WHO Guidelines on Similar Biotherapeutic Products.
http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf; 4. EMA: CHMP Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-Clinical and Clinical Issues (30 May 2012)
40. REMSIMA™/INFLECTRA™ product information accessed February 24, 2014:
1. S. Korea: http://www.celltrion.com/en/BIO/bio01.asp?menu_num=1
2. EMA: http://www.ema.europa.eu/docs/en_GB document_library/EPAR_-_Summary_for_the_public/human/002576/WC500150872.pdf 3. Canadian Product Monograph; Inflextra www.hc-sc.gc.ca
4. USA: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM484859.pdf
5. www.pfizer.ca/node/7526#_ftn1
To extrapolate or not to extrapolate?
There is no unanimous criteria
Indication S Korea 2012 EU 2013 Canada 2014 FDA 2015
Rheumatoid arthritis C C C C
Ankylosing spondylitis C C C C
Psoriatic arthritis E E E E
Psoriasis E E E E
Crohn’s disease E E 2016 E
Ulcerative colitis E E 2016 E
C, approved with a complete data package including a single clinical trial; E, extrapolated indication without a Phase I or III clinical
trial;
-, not approved.
CT-P13 infliximab indications by type of approval
41. Interchangeability and substitution
in different countries
Webinar, February 15, 2012; 2. EMA, Questions and Answers on biosimilar medicines; 3. MHLW Guideline for Ensuring Quality, Safety and Efficacy of Biosimilar Products, March 2009; 4. ANVISA: Resolucao RDC N°55, de 16 de Deem bro de 2010; Diario Oficial da Uniao-Secao 1; N°
n N°7729/2011 (publicado el 21 de Noviembre de 2011); 6. Proyecto de PROY-NOM-257-SSA1-2013; 7. Norma Técnica Nº 170 Sobre Registro Sanitario de Productos Biotecnológicos Derivados de Técnicas ADN Recombinantes; Diario Oificial de la República de Chile, 6 de Septiembre
milar Guidance; 30 July 2013; 9. Health Canada Interchangeability and Substitutability of Subsequent Entry Biologics, July 2010 http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/seb-pbu/01-2010-seb-pbu-qa-qr-eng.php#q15; 10. European Commission: What you need to
know about biosimilar medicinal products. Consensus Information Paper 2013
US1
FDA requirements to meet
interchangeability threshold still
unclear, automatic substitution
of interchangeable drugs to be
determined at state level
Japan3
Interchangeability and
automatic substitution
highly discouraged
EMA2
Decisions on interchangeability
and/or substitution rely on
national competent authorities
and are outside the remit of
EMA/CHMP2,10
Brazil4, Argentina5, Mexico6 Developed guidelines
for biosimilars, but have not yet addressed
interchangeability or automatic substitution
Chile7 Authorities state it is inadequate to substitute
Canada9
Health Canada does not
support automatic
substitution, but allows
provinces to determine
interchangeability
43. Substitution, interchangeability
and medical switching
stitution – Pharmacist action. Physician does not intervene. A and B must be
rchangeable.
ical switching – Treating physician decision
Drug A
Drug B
Drug A
Drug A
Drug B
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm
44. Interchangeability Study
Norway is carrying out a large study
(US$ 3.3 million) in order to see the
mpact of substitution of innovator
nfliximab for biosimilar infliximab.
http://www.biopharma-reporter.com/Markets-Regulations/Norway-to-facilitate-switch-to-biosimilars-with-3m-Remicade-study
46. Phase III study of GP2015 vs. etanercept
in PsO (EGALITY)
cept was EU-licensed Enbrel.
s who achieved at least a PASI 50 response at Week 12 were eligible to enter Period 2.
Griffiths CEM, Thaci D, Gerdes S, et al. Oral presentation. PSO Congress, Paris, France, 7 July 2016.
https//www.clinicaltrials.gov/ct2/results?term=NCT01891864&Search=Search (Accessed June 2016) https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002011-26 (Accessed June 2016)
Study design and disposition of subjects
Period 1:
Double‐blind treatment
GP2015, N=264
(50mg twice weekly)
Etanercept, N=267
(50mg twice weekly)
BL 12Week
1:1 (N=531)R
etanercept (50mg weekly)
52
Period 2: Double‐blind
treatment
GP2015 (50mg weekly)
18 30 36 4224 48
GP2015 c
GP2015 s
Etanercept s
Etanercept c
N=150
N=100
N=96
N=151
Period 3: Double‐blind
extension
N=132N=140
N=142 N=137
N=95 N=88
N=90 N=90S1 S2 S3
Primary endpoint: Equivalence in PASI 75
at Week 12
47. How to consider switching between several
biosimilars?
1. Biologics Price Competition and Innovation Act of 2010; 2. WHO 56th Consultation on International Nonproprietary Names for Pharmaceutical Substances; Executive Summary Geneva, 15─17 April 2013
A biological product may not be evaluated against more than ONE reference product.1,2
Will interchangeability transitivity be applied in practice?
If A=B and A=C, does B=C follow?
Reference product “A” Biosimilar “B”
Biosimilar “C”
B
C
A
Indications with comparative
clinical study?
OR
Indications granted by
extrapolation?
48. Intended Copies: Licensed without biosimilar
regulation. Equivalent efficacy and safety
have not been demonstrated
Manufacturer Intended Copy Examples of countries
where it is (was)
marketed
mab Dr. Reddy Laboratories
(India)
Reditux India
Peru
Ecuador
Chile
Paraguay
Probiomed (Mexico) Kikuzubam Mexico
rcept Shanghai CP Goujian
(China)
Yisaipu
Etanar
Etart
China
Colombia
Mexico
Probiomed (Mexico) Infinitam Mexico
Castañeda-Hernández et al. Joint Bone Spine, 2014; Dörner T et al. Ann Rheum Dis. 2013; Cofepris 2012.
49. SpeB proteolysis with imaged capillary isoelectric
Focusing for the characterization of domain-specific
charge heterogeneities of reference and biosimilar Rituximab
Zichuan Zhang*, Ronel Perrault, Yun Zhao, Julia Ding*
PPD Laboratories, Biopharmaceutical Services, 8551 Research Way Suite 90, Middleton, WI 53562, USA
from India features partially cleaved Lysine residue on the protein C-terminus as well as a lower level of
on. As a demonstration, these results could be applied to the assessment of similarity during biosimilar product
ent…
Journal of Chromatography B, 1020 (2016) 148-157
Rituxan®
Mabthera®
Reditux®
50. Enbrel and Etanercept Intended Copies
M. Scheinberg , G. Castañeda-Hernández, M. Li, U.R.K. Rao, E. Singh, E. Mahgoub, J. Coindreau, J. O’Brien, S. M. Vicik, B. Fitzpatrick, B. Hassett.. Presented at PANLAR, Panama, 2016. and EULAR, London, 2016.
51. http://acrabstracts.org/abstracts/incidence-of-adverse-events-in-patients-treated-with-intended-copies-of-biologic-therapeutic-agents-in-colombia-and-mexico/
Safety of intended copies (ACR 2014)
ract Number:1506 Program: Abstract Submissions (ACR) Year: 2014
Incidence of Adverse Events in Patient Treated
with Intended Copies of Biologic Therapeutic
Agents in Colombia and Mexico
Leonor A. Barile-Fabris1, Fedra Irazoque-Plazuelos2, Ramiro Hernández Vásquez3, Sandra Carrillo Vazquez4 and R. Gúzman5, 1
Rheumatology Department, Hospital Especialidades CMN, Mexico City, Mexico,2 Centro Médico Nacional “20 de Noviembre”
ISSSTE, Mexico City, Mexico,3 Rheumatology, Hospital de Especialidades “Dr. Bernardo Sepúlveda Gutiérrez”, Mexico, Mexico,4
Rheumatology, Hospital Angeles Lindavista, Mexico Df, Mexico, 5 IDEARG, SaludCoop, Bogotá, Colombia.
52. Safety Issues with Rituximab Intended Copy
Comunicado 04/04/2012 http://www.cofepris.gob.mx/AZ/Paginas/Farmacovigilancia/Comunicados.aspx
Anaphylactic Reactions with Rituximab
There are two rituximab products in Mexico.
Analysis of the cases showed that
adverse reactions occurred after the switch
of one product for the other.
53. KIKUZUBAM A RITUXIMAB INTENDED COPY
thdrawn from the Mexican market on March 28, 2014.
ster was revoked due to absence of sound clinical data
on efficacy and to reports of adverse reactions
54. Substitution: Ethical Aspects
Any loss of response is unethical
Baquero et al. Nefrología 2011; 31: 275-285
Time
Therapeuticresponse
Innovator
Unethical
Biosimilar EPO
Substitution
Biosimilar: Ethical
Intended
Copy
55. Conclusions (1)
Biosimilars are not generics, as the active molecule is not identical to that
of the innovator. Biosimilarity is established on the basis of the totality of
evidence: analytical, non-clinical, clinical: including PK, efficacy and safety.
Equivalence clinical studies should be performed in the most sensitive
indication or, if pertinent, in a well-defined and understood population.
Criteria for interchangeability and automatic substitution of innovator and
biosimilar monoclonal antibodies are not universal. This issue is expected
to evolve rapidly in the next years, as more information is available.
56. Intended copies, despite being registered in some countries, are not
biosimilars. Information is not complete. Efficacy and safety may differ from
the innovator. Should be withdrawn.
Biosimilars, but not intended copies, are welcome, as they reduce costs
and increase access.
Conclusions (2)
