Copyright © 2013 Quintiles Biosimilars Knowledge Connect Webinar 4 th November 2013 www.BiosimilarsKnowledgeConnect.com
Copyright © 2013 Quintiles
Biosimilars Knowledge Connect Webinar 4th November 2013
www.BiosimilarsKnowledgeConnect.com
The Biosimilars Investigator Network
Develop and maintain a community of engaged investigators with an interest in biosimilars research
Provide investigators with a comprehensive and up to date set of resources that supports them, their staff and patients in the execution of biosimilars trials
Enable doctors with a relevant interest to gain access to latest information about regulatory processes for biosimilar registration and clinical research
The purpose of the Biosimilars Knowledge Connect program is to:
Biosimilars Knowledge Connect The story so far...
740+ investigators
registered to date across all regions
42 respondents to the
Biosimilars Knowledge Connect Community
survey (Q1 2013)
65% of survey responders rating the
website as ‘helpful’ or ‘very valuable’
Quarterly newsletters • Re-designed Biosimilars Knowledge Connect website including: > Biosimilars study update section > Congress update section > Variety of resource libraries including
video, newsletters and written resources
Localized investigator guides for Europe, Asia and the
Americas
Slide resource deck offered to all who
register
Biosimilars Knowledge Connect program factsheet
• Upcoming in 2013 Q4: > 2 KOL discussion videos > 2 Educational webinars
Agenda Topic Presenter Time
Regulatory Update: Focus on US/EU requirements
Dr Kamali Chance, Senior Director
Head of Global Biosimilars Regulatory Strategy
20 Minutes
Q & A 5 Minutes
Global Biosimilar Development and impact on clinical practice
Dr John Patava, Senior Director
Head of Biosimilars Intelligence and Capabilities
20 Minutes
Q & A 5 Minutes
Closing remarks
Copyright © 2013 Quintiles
Biosimilars: Focus on US/EU Requirements
Kamali Chance, MPH, PhD, RAC Senior Director, Head, Global Biosimilars Regulatory Strategy
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Overview
• What are biologics/biosimilars? Terminology Innovator Biologics Biosimilar ≠ Generic Approved Biosimilars and Alternative Biologics
• Pathway to Market: US and EU Biosimilar Development Definition of Biosimilarity Biosimilar Guidelines in the EU and US Generics vs. Biosimilars Biosimilars: Quality, Non-clinical and Clinical Considerations Risk Factors that Can Affect Immunogenic Response Biosimilar Product Development Extrapolation to Other Indications
• Q & A
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What are Biologics/Biosimilars?
8
Terminology
Terminology Synonyms Definition
Biologic Product
• Virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except chemically synthesized polypeptides), or analogous product applicable to the prevention, treatment, or cure of a disease or condition in humans
Originator • Reference • Innovator • Comparator
• Novel biological medicine that has been patented
Biosimilar • Follow-on biologic (USA) • Bioequivalent biologic • Subsequent entry biologic
(Canada) • Biocomparable (Mexico)
• Biologic medicine with identical primary amino acid sequence to an originator medicine
• Developed with intention to be as close to originator as possible
• Demonstrated similarity in physiochemical characteristics, efficacy, and safety
Copy Biologic • Alternative biologic
• Copy of an originator medicine that has been approved in a country where no official biosimilar regulatory pathway exists or existed
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Innovator Biologics
All trademarks mentioned herein are the property of their respective owners
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Biosimilar ≠ Generic
Biosimilars
Generics Proof of quality and bioequivalence No substantial clinical data required Reference to originator’s data
Different manufacturing processes can and often do yield differences in the end product
After the quality of a biological medicine is demonstrated, some non-clinical and clinical studies are necessary
Immunogenic response cannot be predicted and therefore must be tested
Source: J. Mascaro: Regulatory evaluation of therapeutic biological medicines, Aug 15, 2007
Small molecule
Biological medicine
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2012/2013 Global Clinical Use of Biosimilars and Alternative Biologics
Country Companies Marketed
biosimilars/follow-on biologics
Marketed alternative biologics
USA
Sandoz, Momenta, Merck (Bioventures Division), Pfizer, Lilly, Janssen, Protalix, Biotherapeutics, Momenta Pharma, Hospira, Itero, Phage Biotech, Baxter, Pharmacia-Upjohn, Teva
GH, heparin, rGlucagon, Calcitonin-Salmon, hyaluronidase, G-CSF
EU
Sandoz, Hexal, Teva, Biopartners, Medice Arzneimittel Pütter , CT Arzneimittel, Ratiopharm , AstraZeneca, GSK, Novo Nordisk, Sanofi Aventis, Hospira
GH, EPO, G-CSF, somatropin hGH
Japan Sandoz, Daiichi Sankyo (Ranbaxy), JCR, Kissei, Nippon Kayaku, Nipro, Otsuka Holdings, Roche, Nektar Therapeutics
GH, G-CSF, GM-CSF, IL-2, Zenotech , EPO-kappa, IFNa
India
Bharat Biotech International, Dr. Reddy's Laboratories, Shantha Biotechnics Ltd, Wockhardt, Biocon, Intas Biopharmaceuticals, Lupin, Reliance Life Sciences, Zydus, Intas, Ranbaxy, Sanofi, CP GuoJian Pharmaceutical
GH, EPO, G-CSF, Peg-GSF, IFNa, insulin, teriparatide, mAbs, Regen-D (rhEGF), Indikina, se (strepto-kinase), Glargine, Lispro, Aspart, EPO, G-CSF, streptokinase, Rituximab, IL-2, IFNb, Etanercept
China
Beijing Tri-Prime Genetic SinoBiomed Inc., Shanghai Sunway Biotech, 3SBio Inc., Shenzhen Kexing Biotech, Amoytop Biotech Co. Ltd., CP GuoJian Pharmaceutical, GeneScience Pharmaceuticals, Simcere Pharmaceuticals, Tonghua Dongbao, Wanbang Biopharmaceuticals
GH, EPO, G-CSF, PEG-GSF, IFNa, IL-2, IL-11, insulin, Etanercept, mAbs
Source: Datamonitor strategic analysis pipeline trends December 2011; ADIS, EvaluatePharma and PharmaProjects May 2013
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Country Companies Marketed biosimilars
Marketed alternative biologics
Mexico Probiomed, SICOR Biotech UAB, Pfizer rEPO, R IFN alpha2B IFN alpha2A , rHu G-CSF, Taliglucerase alfa
Brazil
Instituto Butantan, FK Biotecnologic, Bio-Manguinhos, Novo Nordisk, Pfizer, Aspen Pharmacare, Cristália, Enzon Pharmaceuticals, Silvestre Labs
Rh insulin, rEPO-α, monoclonal antibodies, Taliglucerase alfa, PEG-IFN alpha2b, G-CSF, EPO
Israel Teva HGH, IFN alpha2B, G-CSF
Switzerland Biopartners, JW Group Rh-insulin, rhGH, EPO-beta
Canada Cangene, Biocon, Celltrion, Hospira, Roche, Nektar Therapeutics, Sandoz
hGH, R Insulin glargine, EPO-zeta, PEG-IFN alpha2A
Germany Stada, Medice Arzneimittel Pütter EPO-zeta, EPO
S. Africa Bioclones EPO
S. Korea LG Lifescience, Daewoong, Dong-A , Celltrion, Boryung Group, CJ (CheilJedang), Genexine, Hanlim Pharm
Epogen, hGH, EPO, EGFR, GCSF, IFN alpha2A, follitropin, infliximab, EPO-alpha, hCG
Source: Datamonitor strategic analysis pipeline trends December 2011; ADIS, EvaluatePharma and PharmaProjects May 2013
2012/2013 Global Clinical Use of Biosimilars and Alternative Biologics
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Pathway to the Market: US and EU Biosimilar Development
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Definition of Biosimilar/Biosimilarity
A similar biological or 'biosimilar' medicine is a biological medicine that is similar to another biological medicine that has already been authorized for use and it does not have any meaningful differences from the reference medicine in terms of quality, safety or efficacy. Article 8 of Directive 2001/83, as amended.
The PHS Act defines biosimilarity “to mean 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.” Section 7002(b)(2) of the Affordable Care Act, amending section 351(i) of the PHS Act.
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-http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c -The BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March 2010. -US FDA:. Guidances for industry. Quality and Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance Feb 2012.
2004 2009 2011 2006 2007 2008 2012 2010 2013 2005
EMEA Legislative Pathway
EMEA Regulatory Guidance [Overarching Guideline] under revision
Product Class Specific Guidelines: Low molecular weight heparin, recombinant Interferon-alpha
Product Class monoclonal antibodies: non-clinical and clinical issues
Guidelines under revision: Follicle stimulating hormone, Interferon-beta
Product Class Specific Guideline: Erythropoietin (revised)
Quality Guideline; Non-Clinical & Clinical Guideline (under revision )
Product Class Specific Guidelines: Insulin, G-CSF, Somatropin
Product Class Immunogenicity assessment of monoclonal antibodies
PHS Act amended to allow the approval of biosimilars
Overarching Draft Guidelines on biosimilars
Draft revisions to overarching guidelines and nonclinical and clinical guidelines
Europe USA
Biosimilar regulations in EU and USA: different stages of development
• The EU pioneered the development of biosimilar regulations • US overarching guidelines issued
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Generics vs. Biosimilars
Parameter Generics (chemical drugs) Biosimilars
Production source
Chemical synthesis
Living organisms, i.e. cultured yeast, bacteria or animal/plant cells
Active pharmaceutical ingredient
Must be identical to the reference product
Same primary amino acid sequence, the biosimilar active pharmaceutical ingredient is not identical to the reference product
Development batches One batch Generally more than three batches
Characterization Non-comparative Compared with reference product
In vitro non-clinical testing No Yes, compared with the reference product
Non-clinical animal testing No
• Comparative PK/PD (if PD marker is available) in relevant species
• One comparative repeat dose toxicity study in relevant species. If the relevant species is non- human primates, FDA/EMA generally do not require an in vivo non-clinical study unless it is absolutely needed
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Generics vs. Biosimilars
Parameter Generics (chemical drugs) Biosimilars
Clinical – Phase I study Comparative PK/PD (if PD marker available) study in healthy volunteers
Comparative PK/PD (if PD marker available) in healthy volunteers or patients – scientific justification required
Clinical – Phase III studies: safety (including immunogenicity) and efficacy
No
Comparative clinical study(ies) required against the reference product; number of studies required will depend upon the mechanism of action (MOA) for all indications. The number of studies required is assessed by regulators on a case-by-case basis
Pharmacovigilance plan Generally not required, but depends on the drug
Generally required, often mimics reference product’s requirements, but may include additional data for the biosimilar
Post-marketing studies Generally not required Often may be required for late developing adverse events.
Pediatric studies No
In the USA, pediatric studies must be addressed for a biosimilar; however, they are not required for products found to be interchangeable. Not required in the EU.
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Biosimilars: Quality
What should be characterized and compared with reference product? > Comparison of physicochemical parameters (multiple lots of reference products and
biosimilar) » Primary structures, such as amino acid sequence » Higher order structures, including secondary, tertiary, and quaternary structure
(including aggregation) » Enzymatic post-translational modifications, such as glycosylation,
phosphorylation, deamidation and oxidation, among others » N or C terminal truncations; charge variations (isoforms) » Degradants and impurities
> Stability profile
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Biosimilars: Non-clinical Studies
What should be compared with reference product? > In vitro studies – generally performed to assess any possible differences in
bioactivity - Binding to target antigen - Binding to receptors - Fab associated functions (e.g. neutralization, receptor activation or receptor
blockade) - Fc-associated functions (ADCC and CDC assays, complement activation)
> Safety pharmacology, reproduction, mutagenicity and carcinogenicity are generally not required
> In vivo studies – depend upon the need for additional information (residual uncertainty), and the availability of a relevant animal model - Generally, 28-day repeat dose toxicity study is required. If a relevant animal
model not available, determine if transgenic animals or transplant models are available.
- If the relevant animal model is a non-human primate, FDA/EMA generally do not require an in vivo non-clinical study unless it is absolutely needed
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Clinical Safety & Pharmacovigilance
Type of data required: > Comparison of type, frequency and severity of adverse events
> Assessment of anti-drug antibodies, including neutralizing antibodies (immunogenicity assessment)
> Because all differences cannot be detected pre-licensing, a risk assessment will need to be provided for late-occurring safety events seen for the innovator product
> Risk management/pharmacovigilance plan may be required:
- Any PhV measures for the reference product generally will need to be adopted for the biosimilar product
- Any differences seen for the biosimilar product will also need to be addressed
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Immunogenicity: Risk Factors that Can Affect Immunogenic Response
• Underlying disease
• Immune status
• Concomitant medications
• Genetics
• Age
• Dosing schedule
• Route of administration
• Previous exposure to related
proteins
• Manufacturing process
• Varying glycosylation
• Degradation products
• Formulation
• Structural homology
• Post translational modifications
• Chemical modifications
• Impurities from host cells
• Stability
Patient Related Product Related
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Biosimilar Product Development
Both agencies expect a step-wise development plan that can ensure similarity/comparability at each step. The reference product (active comparator) has to be sourced from the respective region. All assessments will be two-way comparability.
> Chemistry Manufacturing and Controls – Analytical comparability
> Non-clinical comparability – in vitro and in vivo (if relevant animal model is available)
> Human PK/PD (if PD biomarker is available) comparability data
> Immunogenicity comparability data
> Efficacy and Safety comparability data
If US or EU only
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Biosimilar Product Development
• Both agencies expect a step-wise development plan that can ensure similarity/comparability at each step.
• Three-way comparability for the following:
> Chemistry Manufacturing and Controls – Analytical comparability > Non-clinical comparability – in vitro and in vivo (if relevant animal model is available) > Human PK/PD (if PD biomarker is available) comparability data
• Two-way comparability for the following (reference product can come from either region):
> Immunogenicity comparability data > Efficacy and Safety comparability data
If both for US and EU
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Extrapolation to other Indications
• The mechanism of action (MOA) in each condition of use for which licensure is sought may include the following:
> The target/receptor(s) for each relevant activity/function of the product > The binding, dose/concentration response, and pattern of molecular
signaling upon engagement of target/receptor(s) > The relationship between product structure and target/receptor interactions > The location and expression of the target/receptors(s)
• The PK and bio-distribution of the product in different patient populations; PD measures may provide important information on MOA
• Differences in expected toxicities in each condition of use and patient population
• Any other factor that may affect the safety or effectiveness of the product in each condition of use and patient population for which licensure is sought
Biosimilar Medicine Development
Considerations and Impact on Clinical Practice
Dr John Patava, Director, Head of Biosimilar Intelligence and Capabilities
Annual Cost of Herceptin vs. Per capita GDP
Source: IMF, Hyundai Securities
List of major biologics by global revenues: Patent expiry products
Source: EvaluatePharma 2012, GaBI, FierceBiotech, GenNews
Brand Name Generic Name Company Revenues 2012 Patent Expiry US
Patent Expiry Ex-US
Humira adalimumab Abbott Laboratories 9,627 31/12/2016 16/4/2018
Enbrel etanercept Amgen 8,519 22/11/2028 1/2/2015
Remicade infliximab Merck & Co. 7,642 4/9/2018 13/8/2014
Rituxan rituximab Roche 7,155 1/1/2018 12/11/2013
Lantus insulin glargine Sanofi 6,378 12/2/2015 30/11/2014
Herceptin trastuzumab Roche 6,283 18/6/2019 28/7/2014
Avastin bevacizumab Roche 6,149 4/7/2019 21/1/2022
NovoLog insulin aspart Novo Nordisk 2,711 7/12/2014 31/12/2017
Tysabri natalizumab Elan 2,457 26/4/2017
Aranesp darbepoetin alfa Amgen 2,040 1/1/2024 1/1/2016
Erbitux cetuximab Bristol-Myers Squibb 1,843 13/2/2016 29/6/2014
Xolair omalizumab Roche 1,793 31/12/2018 31/12/2017
Introduction of biosimilar products drives down cost of biological medicines
Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (McCamish M and Woollett G. The state of the art in the development of biosimilars. 91(3):405–417), © 2012
Biosimilars can improve healthcare • Biosimilars can enable previously restricted therapies to become part of the accepted
standard of care • In the UK, patients have benefited from lower acquisition costs and improvements in
the practice of medicine after the approval of a filgrastim biosimilar • This has enabled the routine use of filgrastim (as a biosimilar) as a first-line treatment
for the first time
-2 -5
13
17
2007 2008 2009 2010
November 2008
biosimilar approved
Note: Zarzio® (filgrastim) is not marketed in the United States.
UK filgrastim volume growth percent change vs. previous year
• Many physicians moved filgrastim back to first-line cancer treatment because of lower biosimilars cost
• G-CSF prevents hospital readmission owing to infection
• Biosimilars are less expensive than originator biologics
• Zarzio “patient support kits” expand patient access: – Patients self-administer at home – Efficiency savings repatriated
Planning biosimilar clinical trials
Drug development paradigm turned upside down
Clinical Trials
PK/PD
Pre-Clinical
Analytical
Originator Development Biosimilar Development
Difference between originator and biosimilar development
Drug Discovery
Factors Influencing Clinical Trial
Design
Safety experience of the innovator
product
Biological class
Molecular weight
Molecular complexity
Nature of the indication and
patient populations
Complexity of endpoints of pivotal trials for innovator
How well mechanism of action and targets of innovator have been
characterized
Immunogenicity of the innovator
Existence of reliable biomarkers
Factors Influencing Biosimilars Trial Design
Same Biosimilar Product: Different Indications
Indication* Rheumatoid Arthritis Psoriasis
No. of enrolled subjects 600 300
No. of sites 115 64
No. of countries 14 8
Duration of trial 27 months 18 months
Cost 100% 40%
Biological medicines that act through inhibition of TNF-α activity are indicated for multiple clinical conditions including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and psoriasis
*Two evaluations were consistent wrt to Statistical plan. Test was equivalence, Similar assumptions for margin and power.
Buy-in from regulatory agencies
• The FDA encourages sponsors and applicants to use the meetings described in this guidance to optimize product development and facilitate submission of marketing applications
• Companies can request scientific advice or protocol assistance either during the initial development of a medicinal product before submission of a marketing-authorization application or later on, during the post-authorization phase
Participating in Biosimilars Research
• Benefits of biosimilars research to patients: – Regulatory agencies have given careful consideration to patient safety in
putting together biosimilar regulatory guidelines – During clinical trials, patients have access to an active medicine, either
biosimilar or originator. There is no placebo arm – Increase affordability and accessibility to biological medicines – Enable previously restricted therapies to become part of the accepted
standard of care – Allow these medicine to be used earlier to treat patients – Enable more patients to be treated for the same drug budget, and free more
resources to be used elsewhere
Biosimilars Knowledge Connect
• Launched in October 2012, Quintiles Biosimilar Knowledge Connect seeks to: – Proactively educate investigators and site staff about biosimilars in 30
countries – Establish a global network of study sites, Biosimilar Investigator Connect – Improve site recruitment and retention – Prepare operational staff
• BiosimilarsKnowledgeConnect.com – Fact sheets, Q&A – Physician guide – Patient education tools – Learning modules – Videos of Quintiles and industry KOLs – Quarterly newsletters
Educating and building the biosimilar sites of today and tomorrow
Over 740 investigators have registered with Biosimilars Investigator Connect (Oct 2013)
Thank You For Your Participation
• Thanks to Kamali for a great summary of the regulatory pathways for biosimilar development and registration – Serves to give great confidence in the oversight of
biosimilar development • There is good evidence to suggest that biosimilar
products have a role to play in future clinical practice – Opportunity for broader access and application of
biological medicines
Copyright © 2013 Quintiles
Biosimilars Knowledge Connect Webinar 4th November 2013
www.BiosimilarsKnowledgeConnect.com