0
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, e...
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 s...
What is a biosimilar?
• Similar to the reference medicine
– Does not have any meaningful differences from
the reference me...
How can a biosimilar differ from its
comparator?
• Microheterogeneity
– alternative disulfide pairings/disulfide shuffling...
Summary of approval process for small molecule
generics, new biologics and biosimilars
Small molecule
generic
New biologic...
Costs of developing a generic vs
biosimilar
• Generic: US$ 1−2 million and up to three years to
bring a standard generic t...
Mark McCamish and Gillian Woollett. mAbs 3:2, 209-217; March/April 2011; © 2011 Landes Bioscience.
European Biosimilar Gui...
TGA Guideline: Evaluation of
biosimilars
• A biosimilar or similar biological medicinal
product (SBMP) is a version of an ...
TGA Guideline: Evaluation of
biosimilars
Submissions for licensing must provide :
– chemistry, manufacturing and quality c...
TGA Guideline: Maintenance of
biosimilarity
• Provide evidence to demonstrate the biosimilar
manufacturer has established ...
The TGA and EMA
• TGA has adopted most of the EMA Guidelines
on assessment of biosimilars
• Minor modifications, related t...
EMA guidelines adopted by TGA
1. General Guidelines
Guideline on similar biological medicinal products containing biotechn...
EMA guidelines adopted (or being considered)
by TGA
3. Specific guidelines – not yet adopted
TGA has the following guideli...
Development of a biosimilar
Mark McCamish and Gillian Woollett. mAbs 3:2, 209-217; March/April 2011; © 2011 Landes Bioscie...
Sandoz: bG2 glycan structure of an unnamed
originator biologic
Mark McCamish and Gillian Woollett. mAbs 3:2, 209-217; Marc...
Biosimilar approvals in the EU
• Approvals 2006-13
– Epoetin 5
– Filgrastim 8
– Somatropin 3
• Approvals 2013/14
– Follitr...
Biosimilars approved by the TGA in
Australia
Product name Active substance Major therapeutic
area
Authorization
date
Manuf...
Monoclonal antibodies (mAb)
Fab
Fc
Antibody molecules
HH
L L
Fc piece
• Comprise 2 heavy
and 2 light chains
• Can be IgG, IgA, IgM,
IgD, IgE
• Can have k or ...
‘Humanised’ or human monoclonal
antibodies
Chimaeric
Reshaped
Key mAb Biologics
Product Indication
Patent Expiry
US EU
Bevacizumab (Avastin) Cancer (colon, breast) 2019 2022
Trastuzuma...
Non-clinical studies - Step 1: in vitro
studies
• In vitro non-clinical studies should be performed with an
appropriate nu...
Non-clinical studies - Step 2:
determination of need for in vivo studies
• It is acknowledged that some mAbs may mediate
e...
Non-clinical studies – Step 3: in vivo
studies
• If an in vivo study is deemed necessary, the focus of the
study (PK and/o...
Clinical studies – Step 1:
Pharmacokinetics
• Usually healthy volunteers, but can be patient
group
• Pharmacodynamics: if ...
Clinical studies – Step 2: Clinical trial
• Phase III trial in one patient group
• Establishing safety and efficacy in one...
Immunogenicity
• The main problems are lack of efficacy and
immune reactions
• Rates of antibody formation similar with tw...
Pharmacovigilance
• A risk management plan, including immunogenicity
assessment, should be in place for all biologics, inc...
Particular problems in
Pharmacovigilance
• Mostly, these are S100 drugs
• Tenders, bulk purchasing
– Hospitals (Victoria)
...
Patient DG: Hb & EPO
0
2
4
6
8
10
12
14
16 30/05/2000
20/06/2000
18/07/2000
12/09/2000
30/11/2000
20/12/2000
1/02/2001
3/0...
Year of PRCA Occurrence
'89 '90 '91 '92 '93 '94 '95 '96 '97 '98
'99 '00 '01 '02
0
10
20
30
40
50
60
1 1
10 15
54
3
Year
10...
Licensing of two infliximab (Remicade)
biosimilars by EMA
• June 2013
• Indicated for treatment of rheumatoid arthritis,
a...
Trials involving potential Rituximab
biosimilars
Sponsor Disease Phase Enrolment Design
Merck & Co RA
NHL
I
I
180
22
RCT v...
Summary
• Biosimilars are growing fast
• Monoclonal antibodies are the most rapidly
growing area
• The TGA has developed c...
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David Power, Austin Health, Heidelberg - Licencing and Prescribing Biosimilars: Evaluation Frameworks

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David Power delivered the presentation at 2014 Pharmaceutical Law Conference.

The Pharmaceutical Law Conference is the foremost meeting place and networking hub of the pharmaceutical law industry, and the only pharmaceutical law event in the Asia-Pacific region. The 2014 event highlights included pharma law reform, IP, competitive strategies, industry transparency, sustainable drug pricing and patenting life sciences and more.

For more information about the event, please visit: http://www.informa.com.au/pharmalawevent14

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  1. 1. Licensing and prescribing biosimilars: Evaluation frameworks David Power Austin Health
  2. 2. 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
  3. 3. Mellstedt H. EJC supplements 11, no. 3 (2013) 1–11 Relative complexity of biologic agents
  4. 4. 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
  5. 5. 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
  6. 6. 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)
  7. 7. 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 Mellstedt H. EJC supplements 11, no. 3 (2013) 1–11
  8. 8. 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 Mellstedt H. EJC supplements 11, no. 3 (2013) 1–11
  9. 9. Mark McCamish and Gillian Woollett. mAbs 3:2, 209-217; March/April 2011; © 2011 Landes Bioscience. European Biosimilar Guidelines
  10. 10. 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.
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. Development of a biosimilar Mark McCamish and Gillian Woollett. mAbs 3:2, 209-217; March/April 2011; © 2011 Landes Bioscience.
  17. 17. Sandoz: bG2 glycan structure of an unnamed originator biologic Mark McCamish and Gillian Woollett. mAbs 3:2, 209-217; March/April 2011; © 2011 Landes Bioscience.
  18. 18. 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 Numberofapprovals GaBI Journal posted 17/01/2014
  19. 19. Biosimilars approved by the TGA in Australia Product name Active substance Major therapeutic area Authorization date Manufacturer/Co mpany 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
  20. 20. Monoclonal antibodies (mAb) Fab Fc
  21. 21. Antibody molecules HH 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
  22. 22. ‘Humanised’ or human monoclonal antibodies Chimaeric Reshaped
  23. 23. 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
  24. 24. 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
  25. 25. 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. Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-clinical and Clinical Issues EMA/CHMP/BMWP/403543/2010
  26. 26. 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. Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-clinical and Clinical Issues EMA/CHMP/BMWP/403543/2010
  27. 27. Clinical studies – Step 1: Pharmacokinetics • Usually healthy volunteers, but can be patient group • Pharmacodynamics: if a suitable system can be identified Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-clinical and Clinical Issues EMA/CHMP/BMWP/403543/2010
  28. 28. Clinical studies – Step 2: Clinical trial • Phase III trial in one patient group • Establishing safety and efficacy in one population Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies – Non-clinical and Clinical Issues EMA/CHMP/BMWP/403543/2010
  29. 29. 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
  30. 30. 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. Mellstedt H. EJC supplements 11, no. 3 (2013) 1–11
  31. 31. 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
  32. 32. Patient DG: Hb & EPO 0 2 4 6 8 10 12 14 16 30/05/2000 20/06/2000 18/07/2000 12/09/2000 30/11/2000 20/12/2000 1/02/2001 3/04/2001 20/06/2001 3/07/2001 4/07/2001 23/07/2001 24/07/2001 1/08/2001 29/08/2001 3/09/2001 11/09/2001 8/10/2001 15/10/2001 24/10/2001 20/11/2001 27/11/2001 4/12/2001 11/12/2001 8/01/2002 11/01/2002 30/01/2002 18/02/2002 Hbg/dl 0 5000 10000 15000 20000 25000 30000 35000 Haemo- globin(gram s/dl) Erythro- poietinDose IU/wk
  33. 33. Year of PRCA Occurrence '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 0 10 20 30 40 50 60 1 1 10 15 54 3 Year 100,000Patient-Year '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 0.0 0.5 1.0 1.5 2.0 2.5 0.18 0.32 0.43 0.54 0.68 0.93 1.1 1.32 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
  34. 34. 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
  35. 35. 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
  36. 36. 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
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