1. CEMDC-PharmaTrain, Module 8. FOLLOW-ON DRUGS:
GENERIC, BIOSIMILAR & NON-BIOLOGICAL SIMILAR MEDICINAL PRODUCTS
May 11th 2017
Marketing authorization of biosimilar medicinal products. Differences of the EMA and FDA regulations
Ildiko Aradi, PhD
Clinical Development of Biologics
Biotechnology Business Unit
Gedeon Richter Plc.

2. AGENDA Registration of biosimilars in the EU
Registration of biosimilars in the US
Harmonisation of regulatory requirements

3. Registration of biosimilars in the EU

4. Biosimilars
Biologicals: made by or derived from living organism using biotechnology (proteins, monoclonal antibodies)
Biosimilars: after patent expiry, e.g. insulin 2001, somatropin 2003, erythropoietin 2004, filgrastim 2006
Legal basis in EU /2004, first biosimilar guidelines /2006
Biologicals form a significant portion of the pipelines
 future for biosimilars

5. Biosimilars in EU First biosimilar in 2006 – somatropin (Sandoz)
First biosimilar mAb in 2013 – infliximab (Remsima/Celltrion and Inflectra/Hospira)
Biosimilar mAbs in focus
Targeted therapies
Market potential
Increasing number of biologicals
Access to patients
Source: Evaluate Pharma, AAPS Biotechnology Conference May 2011

7. Focus on Biosimilars - EMA Definition
A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the European Economic Area (EEA).
Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established. EMEA/CHMP/BMWP/42832/2005 Rev1

8. Biosimilars - Why Not Identical?
MAb
Daltons
Insulin
5 700 Daltons
Complexity matters

9. Major Indications for mAb Therapy
Psoriasis
etanercept (Enbrel®)
adalimumab (Humira®)
infliximab (Remicade®)
Oncology
cetuximab (Erbitux®)
bevacizumab (Avastin®)
rituximab (MabThera®)
trastuzumab (Herceptin®)
Rheumatoid arthritis
rituximab (MabThera®)
adalimumab (Humira®)
etanercept (Enbrel®)
infliximab (Remicade®)
Inflammatory bowel disease
infliximab (Remicade®)
adalimumab (Humira®)
Patent protections expiring soon

11. Duration of procedure:
Centralized Marketing
Authorization procedure
Day 120 List of Questions (LoQ)
Day 180 List of Outstanding Issues (LoOSI)
Duration of procedure:
~ 1 year
Schneider 2008

12. Development of Biosimilar Medicines in EU – Comparability Exercise
EU Reference Product
Comparable
Comparable
Comparable
Target
Process
Physico-chemical quality
Non-clinical
Clinical
Risk Management Plan
Similar Biological Medicinal Product

13. Continuous revison of guidelines
EMA Biosimilar guidelines
PRODUCT SPECIFIC BIOSIMILAR GUIDELINES
GUIDELINES OF RELEVANCE FOR BIOSIMILAR MEDICINES
OVERARCHING BIOSIMILAR GUIDELINES
GENERAL - Guideline on similar biological medicinal products
QUALITY ISSUES - Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues
NON - CLINICAL AND CLINICAL ISSUES - Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues
Insulin
Somatropinn
G-CSF
EPO
LMWH
IFN -alpha
IFN- beta
FSH
mABbs
OTHER GUIDELINES RELEVANT FOR BIOSIMILARS
COMPARABILITY – QUALITY ISSUES – Guideline on comparability of medicinal products containinig biotechnology derived proteins as active substance: Quality Issue
COMPARABILITY – NON -CLINICAL AND CLINICAL ISSUES - Guideline on comparability of biotechnology-derived medicinal products after change in the manufacturing process: non-clinical and clinical issues
IMMUNOGENICITY - Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins and Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use
Continuous revison of guidelines

14. Comparability Exercise
Comparability of different versions of the active substance of a biological
Manufacturing change
Versions of a product need to be comparable before and after a manufacturing change
Biosimilar development
Biosimilar product needs to be comparable to its reference product
© Christian Schneider, presented at 25th Annual EuroMeeting, Amsterdam, 2013

15. Biosimilars are Systematically Engineered to Match the Reference Product
Define target
Confirmation:
Final comparability
exercise
Development of
Manufacturing process
Target directed approach
Characterize multiple lots of the Reference Product: Changes in the reference product over time provides distribution of acceptable variants
Iterative optimization of all process steps using sophisticated analytical characterization to achieve biosimilarity
Ranking quality attributes based on their criticality
Risk based Approach

16. Non-clinical and Clinical Development 1
PRINCIPLES OF NON-CLINICAL DEVELOPMENT
Step-wise approach – risk based
panel of in vitro assays
in vivo non-clinical studies – usually not needed
Challenges: statistical analysis, complex panel of assays, necessity of in vivo studies in certain regions outside of EU

17. Non-clinical and Clinical Development 2
PRINCIPLES OF CLINICAL DEVELOPMENT
Step-wise approach
comparative pharmacokinetic (PK) and pharmacodynamic (PD) study
comparative efficacy and safety study in one or more indications (extrapolation)
sensitive patient population
endpoint selection
immunogenicity
‘specifically tailored’ clinical programs
Challenges: feasibility of huge trials in oncology setting, necessity of local clinical studies in certain regions outside of EU

18. Biosimilars approved in the EEA have equivalent
Aim of the Biosimilar Clinical Studies: Establishing Clinical Comparability
Comparative PK/PD (i.e. Phase I)
Comparative efficacy/safety/immunogenicity (i.e. Phase III)
Equivalence trials
Clinical studies
single centre or multi-centre
healthy volunteers or patients
n ≈
1 to 3-5 years
How much clinical data is necessary?
How much similarity is necessary?
What should be the study population?
What should be the clinical endpoint?
How big safety database is needed? …
Biosimilars approved in the EEA have equivalent
efficacy and safety with the reference product

19. Weise et al. Biosimilars: What clinicians should know, Blood 2012

20. Weise et al. Biosimilars: Clinicians concerns addressed based on scientific principles
Quality of biosimilars in EU
Biosimilar – why not identical?
Sufficient safety database, including immunogenicity
Efficacy of biosimilars
Extrapolation of indications
Interchangeability/substitution

21. Quality of biosimilars in EU
Biosimilars approved in the EU are of high quality - same quality standards for all biologicals
Comprehensive guality comparability programme assessing physicochemical and functional characteristics of the biosimilar with the reference product

22. Biosimilar – Why not Identical?
Biological products always vary
In the human body
From batch to batch
After manufacturing changes
Between manufacturers
© Christian Schneider, presented at 25th Annual EuroMeeting, Amsterdam, 2013

23. Sufficient safety database, including immunogenicity
General safety experience gained with the reference product applicable to the biosimilar based on demonstrated close similarity
Demonstration of similar physicochemical characteristics, biologic activity, pharmacokinetics, pharmacodynamics/efficacy and safety data, including immunogenicity, allow reasonable reassurance for comparable safety profile
Immunogenicity testing: same requirements for all biologicals, no specific concern with biosimilars

24. Efficacy of biosimilars
Biosimilars are as efficacious as their reference products
Equivalence margins for comparative efficacy studies based on statistical and clinical considerations to exclude any clinically relevant difference
Biosimilars are therapeutic alternatives to their reference products using the same posology for the same indications

25. Extrapolation of indications
Based on the totality of evidence provided by quality, non-clinical and clinical comparability data
High analytical and functional similarity: If there are no differences relevant to the pharmacology of the molecule, it will behave as the reference product in all patient populations
Extrapolation also applies to pre-and post-change products already on the market

26. Interchangeability/substitution
Biosimilars are therapeutic alternatives to their reference products using the same posology for the same indications
Switching: do not lead to change in clinical management
Traceability: pharmacovigilance legislation in EU
Recent developments, e.g. Norway and Finnland
Norwegian switch study (NOR-SWITCH) – initiated in 2014; switch to biosimilar infliximab is almost complete in Norway
Current position of Fimea is that ‘biosimilars are interchangeable with their reference products under the supervision of a health care person’

27. Registration of biosimilars in the US

28. Five distinct registration pathways in the US
EU: Centralized procedure, interchangeability decided at national level
US: Alternative pathways, interchangeability is regulated by FDA
1. NDA (505(b)1): Originator NCE
‘Original’ or‘Stand alone’ - small molecule and early biotechnology products – not a registration route for biosimilars
2. Hybrid NDA (505(b)2): Partial reference to originator NCE
Example : Somatropin/Sandoz ; EU: biosimilars USA: 505(b)2 úton.
No available pathway for biosimilars at that time.
3. ANDA (505(j)): Reference to originator NCE
Example: LMWH /Sandoz; EU: biosimilar USA: ANDA, generic
4. BLA (PHS 351(a)) Originator biologicals
Most biotechnology products registered in the US as BLA.
Example: Tbo-filgrastim/Teva; EU: biosimilar (2008), FDA: BLA (submitted in 2009 and approved 2012, lack of biosimilar pathway)
5. BLA (PHS 351(k)): Reference to originator biological (2010)
1962. után (Kefauver-Harris – safety&efficacy is kell az elfogadáshoz) törzskönyvezett gyógyszerek generikumai esetében.

29. Generic vs biosimilar registration in the US

30. Biosimilar (BLA 351(k)) legislation in the USA
Public Health Service Act - Amended by the Biologic Price Competition and Innovation Act of 2010
Section 351(k) abbreviated pathway for the approval of biosimilars
Section 351(i) definition of biosimilarity
Biosimilar
Interchangeable biosimilar
Definition of biological product redefined to include “protein”. For proteins, BLA 351(k) can be followed.
Chemically synthesized polypeptides with more than 100 amino acids are proteins
Recombinant biologicals with less then 40 amino acids are not proteins but peptides (consequently suitable for ANDA and not for BLA 351(a or k))
Highly similar (USA) used instead of comparable (EU)
ICH Q5E: comparability defined as highly similar quality attributes

31. FDA Definition of biosimilarity
Biosimilar or Biosimilarity means:
that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

32. Definition: Reference Product
Reference Product means:
the single biological product, licensed under section 351(a) of the PHS Act, against which a biological product is evaluated in an application submitted under section 351(k) of the PHS Act.
Note: A biological product, in a 351(k) application, may not be evaluated against more than 1 reference product.

33. Definition: Interchangeability
Interchangeable or Interchangeability means:
the biological product is biosimilar to the reference product;
it can be expected to produce the same clinical result as the reference product in any given patient; and
for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.
Note: The interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

34. FDA guidelines Category Title Type Date Procedural; Biosimilarity
Reference Product Exclusivity for Biological Products Filed Under (PDF - 99KB)
Draft Guidance
08/04/14
Biosimilarity
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (PDF - 169KB)
Final Guidance
04/28/15
Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (PDF - 144KB)
Biosimilars
Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry (PDF - 107KB)
Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (PDF - 104KB)
05/12/15
Biosimilarity; Procedural
Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (PDF - 306KB)
11/17/15
Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (PDF - 150KB)
12/28/16
Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry (PDF - 229KB)
01/17/17

35. BLA 351(k): general concept and issues
Scientific/clinical issue: biosimilar vs interchangeable biosimilar
Biosimilar – no interchangeability
Interchangeable biosimilar – additional clinical studies
BUT first, almost all products will become biosimilar only
Biosimilar – new active ingredient
New INN for biosimilar (originator’s strategy, branded product) just like for BLA
Consequences for pharmacovigilance
Because of new INN PREA requires PK and/or PD study in pediatric population; Solution: FDA meeting, waiver, or postpone
EU biosimilar dossier could be submitted as BLA 351(a) see example of tbo-filgrastim
Patent issues

36. Biosimilar approvals in the US
INN
Trade name
Company
Date of approval
pegfilgrastim
Mylan/Biocon
adalimumab
Boehringer Ingelheim
bevacizumab
Amgen/Allergan
trastuzumab
Coherus
infliximab
Flixabi
Samsung/Merck
Amjevita
Amgen
2016
Sandoz
complete response
letter
etanercept
Erelzi
epoetin alfa
Retacrit
Pfizer/Hospira
filgrastim
Apotex
Inflectra
Pfizer/Celltrion
Zarxio
2015

37. Biosimilars under FDA review
351(k) Applications Under First-Cycle Review
Goal Date
Proposed Biosimilar
Reference Product
January 2017
Samsung Bioepis' SB2
Janssen Biotech's Remicade(infliximab)
June 2017
Coherus’ CHS-1701
Amgen's Neulasta (pegfilgrastim)
September 2017
Mylan and Biocon's MYL-1401O
Genentech's Herceptin (trastuzumab)
Amgen and Allergan's ABP 215
Genentech's Avastin (bevacizumab)
September 2017 (estimated)
Boehringer Ingelheim’s BI
AbbVie’s Humira (adalimumab)

38. Global harmonisation of reguatory requirements
Challenges - need for
comparability with reference product sourced locally
in vivo studies
efficacy data
local studies
Interchangeability
INN name issue
Comparability at clinicallevel is not expcted to be affected by ethnic factors – acceptance of trials from different regions/populations should be justified.

39. Global harmonisation of reguatory requirements
Global harmonisation efforts
WHO
IPRF: International Pharmaceutical Regulators Forum
Biosimilar Cluster: EMA, FDA, HC, PMDA
Global development can be facilitated by acceptance of reference products and clinical data from different regions
Goal: faster access of patients to affordable medicines at sustainable price
Comparability at clinical level is not expcted to be affected by ethnic factors – acceptance of trials from different regions/populations should be justified.

40. European markets - 10 years experience with biosimilars
Clinicians confidence to be further increased to ensure biosimilars can keep their promise of improving patient access and affordability
10 years of experience with biosimilars in the EU: physicians and patients are becoming more confident and less concerned
Education and unbiased information on biosimilars are important
2013: European Commission consensus
information document
2016: Medicines for Europe, Biosimilar Medicines Handbook

41. Limited patient access to biologics

42. Thank you for your attention
Q&A