David Power, Austin Health, Heidelberg - Licencing and Prescribing Biosimilars: Evaluation Frameworks

Licensing and prescribing biosimilars: Evaluation frameworks

David Power

Austin Health

What is a Biologic?

• Any medicinal product manufactured in or extracted from biological sources

– Protein, Sugars, DNA, etc

Girard M, et al. Anal Chim Acta 2012; 713: 7-22

Erythropoietin - Epoetin G-CSF - Filgrastim

Mellstedt H. EJC supplements 11, no. 3 (2013) 1–11

Relative complexity of biologic agents

IMS Health, Thought Leadership, Sept 2013

The world-wide biologics market

Share of total sales

Share of biologics

Global sales of biologics predicted to grow twice as fast as small molecules. Mark McCamish

and Gillian Woollett 2011

What is a biosimilar?

• Similar to the reference medicine

– Does not have any meaningful differences from the reference medicine in terms of quality, safety or efficacy

• Information on safety and efficacy less than that required to register a biological medicine

• Not a superior product (Biobetter)

EMA Website and opinion

How can a biosimilar differ from its comparator?

• Microheterogeneity – alternative disulfide pairings/disulfide shuffling, deamidation,

(methionine) oxidation, crystallization of N-terminal glutamine residues, and partial enzymatic cleavage

• Aggregation • Glycosylation

– Only a problem for glycosylated proteins – Virtually impossible to replicate glycosylation

• Excipients – Solubilisers, such as Tween

• Syringe – A known source of problems (Eprex, Novicrit)

Summary of approval process for small molecule generics, new biologics and biosimilars

Small molecule generic

New biologic agent (full dossier)

Biosimilar (reduced dossier)

Quality Individual quality assessment

Comparison with reference product

Individual quality assessment

Individual quality assessment

Comprehensive comparison with reference product

Pre-clinical No data required Full pre-clinical program

Abbreviated pre-clinical program (tolerance, PK/PD)

Clinical Bioequivalence study

Phase 1 Phase II Phase III in all

indications Risk management

plan

Phase I PK/PD study

Phase III study in a sensitive, representative indication

Risk management plan


Costs of developing a generic vs biosimilar

• Generic: US$ 1−2 million and up to three years to bring a standard generic to market

• Biosimilar: US$ 10−40 million and takes six to nine years to bring a biosimilar to market

• The set-up investment for a novel manufacturing process is estimated at US$ 250–450 million

• Generics are typically marketed at as low as 20% of the brand cost in the United Kingdom (UK), biosimilars are marketed at as high as 70−85% of the brand cost


Mark McCamish and Gillian Woollett. mAbs 3:2, 209-217; March/April 2011; © 2011 Landes Bioscience.

European Biosimilar Guidelines

TGA Guideline: Evaluation of biosimilars

• A biosimilar or similar biological medicinal product (SBMP) is a version of an already registered biological medicine that: – has a demonstrable similarity in physicochemical,

biological and immunological characteristics, efficacy and safety, based on comprehensive comparability studies

– has been evaluated by the TGA according to this guideline and other relevant EU guidelines adopted by the TGA.

TGA Guideline: Evaluation of biosimilars

Submissions for licensing must provide :

– chemistry, manufacturing and quality control data (Module 3)

– preclinical data (Module 4)

– clinical data (Module 5)

– a Risk Management Plan

TGA Guideline: Maintenance of biosimilarity

• Provide evidence to demonstrate the biosimilar manufacturer has established an in-house primary reference standard comparable to the reference preparation in the comparability study.

• Following any subsequent significant manufacturing process changes, the sponsor must provide evidence that the post variation product is comparable to both the in-house primary reference standard and the pre-variation product.

TGA 30 July 2013

The TGA and EMA

• TGA has adopted most of the EMA Guidelines on assessment of biosimilars

• Minor modifications, related to Australian situation, have been made to several

• Approval in the EU does not guarantee approval in Australia

• The Originator Product must be licensed and well used in Australia

EMA guidelines adopted by TGA

1. General Guidelines Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: nonclinical and clinical issues EMEA/CHMP/BMWP/42832/2005 Effective date: 29 September 2006 2. Specific guidelines These guidelines are specific to the type of biosimilar product: Recombinant erythropoietins EMEA/CHMP/BMWP/94526/2005 Corr. Effective date: 29 September 2006 Revision of 2008. EMEA/CHMP/BMWP/301636/2008 not yet adopted by TGA. Effective date: 1 October 2010 Recombinant G-CSF EMEA/CHMP/BMWP/31329/200 Effective date: 29 September 2006 Recombinant human insulin EMEA/CHMP/BMWP/32775/200 Effective date: 12 September 2006 Low molecular weight heparins EMEA/CHMP/BMWP/118264/2007 Effective date: 5 August 2009 Somatropin EMEA/CHMP/BMWP/94528/2005 Effective date: 29 September 2006 Recombinant interferon alpha EMEA/CHMP/BMWP/102046/2006 Effective date: 17 December 2010

GaBI Journal updated 25/04/2014

EMA guidelines adopted (or being considered) by TGA

3. Specific guidelines – not yet adopted TGA has the following guidelines published for information only for specific biosimilar products. These guidelines have not yet been adopted by the TGA. Monoclonal antibodies EMEA/CHMP/BMWP/403543/2010 Under public consultation, effective date: 1 December 2012 4. Other guidelines Other guidelines relevant for biosimilars from the EMA include: Immunogenicity assessment of biotechnology-derived therapeutic proteins EMEA/CHMP/BMWP/14327/2006 Effective date: 22 June 2009 Comparability of Biotechnology-Derived Medicinal Products after a change in the Manufacturing Process - Non-Clinical and Clinical Issues CHMP/BMWP/101695/06 Effective date: 8 April 2009 5. Other guidelines – not yet adopted TGA has the following guidelines published for information only. These guidelines have not yet been adopted by the TGA. Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use EMEA/CHMP/ 114720/2009 Under public consultation, effective date: 15 July 2009 End of consultation: 28 May 2014

GaBI Journal updated 25/04/2014

Development of a biosimilar


Sandoz: bG2 glycan structure of an unnamed originator biologic


Biosimilar approvals in the EU

• Approvals 2006-13 – Epoetin 5

– Filgrastim 8

– Somatropin 3

• Approvals 2013/14 – Follitropin 2

– Infliximab 2

• ‘In the works’ – Follitropin 1

– Insulin glargine 1

2006

2007

2008

2009

2010

2011

2012

2013

2014

0

2

4

6

Year

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ls

GaBI Journal posted 17/01/2014

Biosimilars approved by the TGA in Australia

Product name Active substance Major therapeutic area

Authorization date

Manufacturer/Company name

Aczicrit Epoetin lambda Anaemia 27 Jan 2010 Sandoz

Grandicrit Epoetin lambda Anaemia 27 Jan 2010 Sandoz

Nivestim Filgrastim Cancer 16 Sept 2010 Hospira

Novicrit Epoetin lambda Anaemia 27 Jan 2010 Novartis

Omnitrope Somatropin Dwarfism 29 Sept 2010 Sandoz

SciTropin A Somatropin Dwarfism 29 Sept 2010 SciGen Australia

Tevagrastim Filgrastim Cancer 29 Aug 2011 Aspen

Zarzio Filgrastim Cancer 7 May 2013 Sandoz

GaBI Journal posted 21/02/2014

Monoclonal antibodies (mAb)

Fab

Fc

Antibody molecules

H H

L L

Fc piece

• Comprise 2 heavy and 2 light chains

• Can be IgG, IgA, IgM, IgD, IgE

• Can have k or l light chain

‘Humanised’ or human monoclonal antibodies

Chimaeric Reshaped

Key mAb Biologics

Product Indication

Patent Expiry

US EU

Bevacizumab (Avastin) Cancer (colon, breast) 2019 2022

Trastuzumab (Herceptin) Cancer (breast) 2019 2014

Palivizumab (Synagis) Respiratory syncytial virus 2015 2015

Cetuximab (Erbitux) Cancer (colon, SCC) 2016 2014

Etanercept (Enbrel)* Arthritis 2013/23 2015

Adalimumab (Humira) Arthritis, IBD 2016 2018

Infliximab (Remicade) Arthritis, IBD 2018 2014

Rituximab (MabThera) Lymphoma, CLL, RA 2018 2013

Brinks V. GaBI Journal 2013; 2: 188-93.

*a fusion protein between Fc of IgG and TNF receptor

Non-clinical studies - Step 1: in vitro studies

• In vitro non-clinical studies should be performed with an appropriate number of batches of product representative of that intended to be used in the clinical trial. These studies should include relevant assays on: – Binding to target antigen(s) – Binding to representative isoforms of the relevant three Fc

gamma receptors (FcγRI, FcγRII and FcγRIII), FcRn and complement (C1q)

– Fab-associated functions (e.g. neutralization of a soluble ligand, receptor activation or blockade)

– Fc-associated functions (e.g. antibody-dependent cell-mediated cytotoxicity, ADCC)

– complement-dependent cytotoxicity, CDC; complement activation)

Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-clinical and Clinical Issues EMA/CHMP/BMWP/403543/2010

Non-clinical studies - Step 2: determination of need for in vivo studies

• It is acknowledged that some mAbs may mediate effects that cannot be fully elucidated by in vitro studies. Factors to be considered when the need for additional in vivo non-clinical studies is evaluated, include but are not restricted to: – Presence of relevant quality attributes that have not been

detected in the reference product (e.g new post-translational modification structure)

– Presence of quality attributes in significantly different amounts than those measured in the reference product

– Relevant differences in formulation, e.g. use of excipients not widely used for mAbs.


Non-clinical studies – Step 3: in vivo studies

• If an in vivo study is deemed necessary, the focus of the study (PK and/or PD and/or safety) depends on the need for additional information. Animal studies should be designed to maximise the information obtained. In addition, depending on the endpoints needed, it may not be necessary to sacrifice the animals at the end of the study.

• Studies regarding safety pharmacology and reproduction toxicology are not required for non-clinical testing of biosimilar mAbs. Studies on local tolerance are usually not required.


Clinical studies – Step 1: Pharmacokinetics

• Usually healthy volunteers, but can be patient group

• Pharmacodynamics: if a suitable system can be identified


Clinical studies – Step 2: Clinical trial

• Phase III trial in one patient group

• Establishing safety and efficacy in one population


Immunogenicity

• The main problems are lack of efficacy and immune reactions

• Rates of antibody formation similar with two generic Infliximab drugs licensed in in EU (about 25% in long-term)

• Difference between neutralising and non-neutralising antibodies

Pharmacovigilance

• A risk management plan, including immunogenicity assessment, should be in place for all biologics, including biosimilars.

• As mandated by the World Health Organization (WHO), biosimilars are allocated the same international non-proprietary name (INN), also referred to as a generic name, as their originator biologic.

• Given that biosimilars are similar to but not identical to their originators, there is no scientific basis to substitute a biosimilar for a branded product, and automatic substitution could potentially put patients at risk by preventing adequate traceability or encouraging switching between products.


Particular problems in Pharmacovigilance

• Mostly, these are S100 drugs

• Tenders, bulk purchasing

– Hospitals (Victoria)

– State-wide (Qld, SA)

• Widespread availability

– Multiple public hospitals

– Private/community pharmacies

Patient DG: Hb & EPO

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10000

15000

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25000

30000

35000

Haemo-

globin(gram

s/dl)

Erythro-

poietinDose

IU/wk

Year of PRCA Occurrence

'89 '90 '91 '92 '93 '94 '95 '96 '97 '98

'99 '00 '01 '02 0

10

20

30

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1 1 10 15

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Year

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'89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 0.0

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0.18 0.32 0.43

0.54 0.68

0.93 1.1

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1.6 1.83

2.09 2.26

2.48

.66

Annual Suspected Pure Red Cell Aplasia Cases Reported and Exposure

by Year of Occurrence

1989 - March 31, 2002

Cases Reported

(N=84*)

Exposure

Exposure in 2002 extrapolated based on past data

* 23 cases not included - year unknown Data from JNJ

Licensing of two infliximab (Remicade) biosimilars by EMA

• June 2013 • Indicated for treatment of rheumatoid arthritis,

adult Crohn’s disease, paediatric Crohn’s disease, ulcerative colitis, paediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis

• Remsima (Celltrion) and Inflectra (Hospira) – RA n=606 phase III, for 30 weeks – ankylosing spondylitis n=250

• Pharmacovigilance plan

Trials involving potential Rituximab biosimilars

Sponsor Disease Phase Enrolment Design

Merck & Co RA NHL

I I

180 22

RCT vs Rituximab

Celltrion DLBCL RA

I I

10 147

Open-label RCT vs Rituximab

Sandoz RA I/II 164 RCT vs Rituximab

Pfizer RA I/II 210 RCT vs Rituximab

Samsung Biologics RA I/III 500 RCT vs Rituximab

Teva RA III 544 RCT vs Rituximab

Boehringer Ingelheim RA III 306 RCT vs Rituximab

Vital et al. Expert Opin Biol Ther 2013; 13: 1049-62

Summary

• Biosimilars are growing fast

• Monoclonal antibodies are the most rapidly growing area

• The TGA has developed cogent policies, involving an Australian Overall Guideline and adoption of EMA Guidelines with an Australian context

• Pharmacovigilance is a constantly challenging area

Business

David Power, Austin Health, Heidelberg - Licencing and Prescribing Biosimilars: Evaluation Frameworks