Transcript Biosimilar 2

Biological Products: concepts, naming,
interchangeability,extrapolation and safety
Dr Valderílio Feijó Azevedo, MD, PhD
Universidade Federal do Paraná
Edumed Biotech
Adjunct professor of rheumatology at the Federal
University of Paraná, Brazil .
R & D Director for new biopharmaceuticals products
development at Edumed biotech .
Clinical investigational fees from Pfizer, Roche, Janssen,
Bristol, Abbott, Medimmune, Boehringer, GSK, UCB, Sanofi.
Financial support to participate of meetings and give
conferences to Pfizer, Roche, , MSD, BMS, Merck Serono and
Janssen and Novartis.
Biological Products
I.
Vaccines
II. Antivenom immunoglobulins
III. Blood products
IV. Biomedicines, obtained from:
a) Biological fluids or animal tissues
b) Biotechnological procedures
V. Monoclonal antibodies
VI. Medicines containing live, attenuated or dead microorganisms
VII. Probiotics
VIII. Allergens
Agência Nacional de Vigilância Sanitária - Anvisa
Biologicals are complex molecules
Biologics
small molecule
1.
2.
3.
4.
1x
12x
38x
79x
300x
Imatinib1
~0.5 kDa
Insulin2
~6 kDa
Filgrastim3
~19 kDa
Pegfilgrastim3
~39 kDa
Monoclonal antibody
(e.g. rituximab)4
~150 kDa
Imatinib - Compound Summary. Available from: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5291. Accessed 01 July 2013.
Harvey J. The Open Neuroscience Journal 2007:1:1-6.
Neulasta Product Information. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000420/WC500025941.pdf. Accessed 01 July 2013.
Rituximab Prescribing Information. Available at: http://www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed 01 July 2013.
 Biologics are bigger than generics
Complexity
Estructure
Size
Epoetin
Aspirin
Estability
Microheterogeneity
Small molecule
Biologic –
monoclonal
antibodies
What Are Biosimilars?
A biosimilar is a biologic medicinal product that contains a version of the active substance
of an already authorized original biologic medicinal product (reference medicinal product)
in the EEA (European Economic Area). A biosimilar demonstrates similarity to the
reference medicinal product in terms of quality characteristics, biologic activity, safety,
and efficacy based on a comprehensive comparability exercise.
Committee for Medicinal Products for Human Use. Guideline on similar biologic
medicinal products [draft]. London: European Medicines Agency; 2013.
Biosimilarity means that the biologic product is highly similar to a US-licensed reference
biologic notwithstanding minor differences in inactive components, and for which there
are no clinically meaningful differences in safety, purity, and potency of the product
US Food and Drug Administration. Guidance for industry. Biosimilars: questions and
answers regarding implementation of the biopharmaceutical Price Competition and
Innovation Act of 2009 [draft]. Department of Health & Human Services; 2012.
Biosimilarity is established through a comparability exercise defined as a head-to-head
comparison of a biotherapeutic product with a licensed originator product with the goal to
establish similarity in quality, safety, and efficacy.
Expert Committee on Biological Standardization. Guidelines on evaluation of similar
biotherapeutic products (SBPs). Geneva: World Health Organization; 2009.
7
Biosimilars Are Highly Similar to
Reference Products
• Biosimilars are developed to closely match the
reference product1
Biopharmaceutical
• Version of already authorized
biopharmaceutical
Biosimilar2
• Similar in physiochemical characteristics,
biological activity, PK, efficacy, and safety
• Demonstration of similarity by a
comprehensive comparability exercise
PK = pharmacokinetics.
1. Woodcock J, et al. Nat Rev Drug Discov. 2007;6:437-442.
2. Weise M, et al. Nat Biotechnol. 2011;29(8):690-693.
8
Biosimilar Regulatory Pathways:
Evolving Landscape
Biosimilars regulation enacted
Biosimilars regulation drafted or in development
No biosimilars regulation
Biosimilars regulation status unknown
1. Bennett CL, et al. Lancet. 2014;15:e594-e605. 2. GaBI Online. Biosimilars approved in South Korea. http://www.gabionline.net/Biosimilars/ General/Biosimilars-approved-in-SouthKorea. Accessed February 16, 2015. 3. European Medicines Agency. Remsima. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002576/
human_med_001682.jsp&mid=WC0b01ac058001d124. Accessed February 16, 2015. 4. Health Canada. Remsima Summary Basis of Decision. http://www.hc-sc.gc.ca/dhpmps/prodpharma/sbd-smd/drug-med/ sbd_smd_2014_remsima_160195-eng.php. Accessed February 16, 2015. 5. GaBI Online. Biosimilar infliximab receives approval in Japan and
Turkey. http://www.gabionline.net/Biosimilars/News/Biosimilar-infliximab-receives-approval-in-Japan-and-Turkey. Accessed February 16, 2015. 6. Ropes & Gray. China announces final
biosimilars guideline. http://www.ropesgray.com/news-and-insights/Insights/2015/March/China-Announces-Final-Biosimilars-Guideline.aspx. Accessed March 11, 2015.
Figure adapted from Scheinberg MA, Kay J. Nat Rev Rheumatol. 2012;8:430-436.
9
Biosimilar Pathway Represents a Paradigm Shift
From Standard Originator Registration Pathway
The Objective of a Biosimilar Development Program Is to Establish Biosimilarity
Based Upon Totality of Evidence, Not to Reestablish Benefit1,2
Originator Pathway [§351(a)]3,4
Clinical Studies
Biosimilar Pathway [§351(k)]3,4
Clinical
Studies
Clinical Pharmacology
Clinical
Pharmacology
PK/PD
Preclinical
Preclinical
Analytical
Confirm safety and
efficacy in a disease
population (dose
ranging not
necessary)
Analytical
PD = pharmacodynamics.
1. Schneider CK, et al. Nat Biotechnol. 2012;30:1179-1185. 2. Koslowski S, et al. N Engl J Med. 2011;365:385-388. 3. MacDonald J. Presented at:
APEC: Biotherapeutics Workshop; September 2013. 4. McCamish M. Presented at: EMA Workshop on Biosimilars; October 2013; London, UK.
10
Biopharmaceuticals Are Produced Through
a Highly Controlled Manufacturing Process
• Both originators and biosimilars are produced by living organisms from a
genetic sequence using biotechnology1,2
Medium consists
of sugars, proteins,
and amino acids
Impurities bind to gel
1. Mellstedt H, et al. Ann Oncol. 2008;19(3):411-419. 2. Schellekens H. NDT Plus. 2009;2(suppl 1):i27-i36.
11
Biosimilar Development
Step 1
Step 2
Analytics
Characterization
Process
Development
Preclinical
Clinical
Pharmacology
Ph 3 Clinical
Study
• Targeted preclinical and clinical program1
• Confirm expected similarity in safety and
efficacy profiles2
– Goal: demonstrate neither decreased nor increased
activity relative to the reference product
• Equivalence or at least noninferiority must be demonstrated
• Superiority studies are not appropriate
1. McCamish M, et al. Clin Pharmacol Ther. 2012;91(3):405-417. 2. Weise M, et al. Nat Biotechnol. 2011;29(8):690-693.
12
Biosimilar Development Can Be Thought of as a Stool
Supported by 3 Pivotal Datasets, Generated in a
Stepwise Fashion
Totality of the Evidence (Stool Legs)
Biosimilar
Step 1
Step 3
Comparative analytical
and nonclinical data
PK /PD
Pivotal comparative efficacy/
safety clinical trial;
Stringency applied to trial statistics will
depend on analytical and PK similarity
Step 2
PK/PD clinical studies
TOTALITY OF THE EVIDENCE:
While the majority of “pivotal” data—and the analytical
bedrock of the approval database—are available prior to phase 3
clinical trial, all 3 steps are vital to the final outcome
23
True Biosimilars: Stringent Standards for
Developing, Testing, and Monitoring
Highest
manufacturing
standards1,2
Rigorous testing
for efficacy, safety,
and similarity1
Appropriate
postmarketing
support1
• Expert management of
the complexities of
producing the molecule
• Product efficacy is
equivalent to reference
product
• Perform appropriate
pharmacovigilance
activities
• Similarity using the
latest technology
• Safety and tolerability
are consistent with
reference product
• Monitor stakeholder
experiences with the
product to ensure
safety and efficacy
1. Mellstedt H, et al. Ann Oncol. 2008;19(3):411-419. 2. Schellekens H. NDT Plus. 2009;2(suppl 1):i27-i36.
14
Regulatory considerations:
Naming
 A biosimilar may be approved under the same INN as its reference product
• Use of the INN alone may cause confusion
Prescribing
Originator
(INNimab)
PRESCRIPTION
FORM
Physician
Pharmacist
INNimab
Biosimilar 1
(INNimab)
Biosimilar 2
(INNimab)
Pharmacovigilance
REPORTING
FORM
Biosimilar 1
(INNimab)
Patient
Adverse
event
INNimab
?
?
Figure created from 1,
A naming convention may be needed to distinguish
biosimilar versions from one another and the originator
1. Dorner T, et al. Ann Rheum Dis 2013;72:322–8.
INN, international non-proprietary name.
NAMING OF BIOLOGICS
•
•
•
•
Concept of one single non-proprietary name
World Health Assembly Resolution WHA3.11
More than 10.000 applications.
Drug regulation, prescribing,dispensing,
pharmacopoeias, labelling, pharmacovigilance and
in scientific literature.
HOW TO BUILD AN INN
•
Unusual word
•
Fantasy prefix(two or more syllables)
•
Followed by a stem suffix- indicate chemical or
pharmacological group or substems to refine.
•
Alvelestat. Suffix stat - enzyme inhibitor
•
ele – subclasse of inhibitors
•
alv – fantasy – unique substance
STEMS
Anib- angiogenesis inhibitors(e.g. pazonib)
Anserin – serotonina receptor antagonists (eg
ritanserin and mianserin)
Ase – enzymes (eg asparaginase)
Azepam- benzodiazepines(eg diazepam and
oxazepam)
Cain- class I antiarrhythmics (eg procainamide)
Mab- monoclonal antibodies
INN FOR BIOLOGICALS
1. 11 general policies for specific classes of biological and
biotechnological substances
2.non-glysosilated products- filgrastim
3.Glycosylated produts- epoetin (alpha, beta,zeta,...)
4.Monoclonal antibodies- fantasy prefix, substem 1 indicate the biological
target( tu, li), substem 2(xi, zu, u,) suffix mab
Biosimilars should undergo comparative
clinical trials
Placebo

Randomize
Biosimilar
Reference product
Randomize
Biosimilar

Biosimilar products should be evaluated against the reference product in
comparative head-to-head clinical trials, rather than against a placebo1,2
1. EMA. CHMP/BMWP/403543/2010.
2. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
EMA, European Medicines Agency; FDA, Food and Drug Administration.
Biosimilar clinical trials should aim to demonstrate
equivalence to the reference product
Treatment difference (Δ)
0



Non-inferiority study
Superiority study
Equivalence study
Inferior (Δ < 0)
Pre-defined margin
95% CIs of Δ must
fall within these
margins
Superior (Δ > 0)
Figure adapted from 3
Equivalence testing is the preferred design for establishing biosimilarity*1,2
*Non-inferiority studies may be acceptable in
some cases, if properly justified.1
1. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
2. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies –
non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010.
3. Lesaffre E. Bull NYU Hosp Jt Dis 2008;66:150-4.
CI, confidence interval; EMA, European Medicines Agency;
FDA, Food and Drug Administration.
Indication extrapolation: Concept
Innovator product
Pivotal Phase III trials:
RA trial
AS trial
PsA trial
PsO trial
Biosimilar
Approval
Approved indications:
RA
AS
PsA
PsO
Innovator products can
only be approved for
indications in which they
have been studied in
Phase III clinical trials
Approved indications:
RA
AS
PsA
PsO
Biosimilars can be
approved for all of the
same indications as the
reference product, on the
basis of biosimilarity in
one Phase III clinical trial
Approval
Pivotal Phase III trials:
RA trial
Extrapolation of
the reference
product’s data
Theoretical example.
Figure created from 1,2
1. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
2. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies –
non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010.
AS, ankylosing spondylitis; EMA, European Medicines Agency;
FDA, Food and Drug Administration; PsA, psoriatic arthritis;
PsO, psoriasis; RA, rheumatoid arthritis..
Global Guideline – Extrapolation of Indication
<Extrapolation of Indication>
Topic
Extrapolation
of Indication
Reference
EU
US
For recombinant proteins, in
certain cases, it may
be possible to extrapolate
therapeutic similarity
to other indications.
Justification of
extrapolation
depends on clinical
experience, available
literature, whether the same
mechanism of action or
receptor is involved in
both indications, and
possible safety issues in
different subpopulations.
The sponsor will need to
provide sufficient scientific
justification for
extrapolating clinical data
to support a determination
of biosimilarity for each
condition of use for which
licensure is sought. Such
scientific justification
should address, for
example, the following
issues for the tested and
extrapolated conditions of
use.
The MOA(s) in each
condition of use for which
licensure is sought.
The PK and biodistribution of the
product in different
patient populations; PD
measures may provide
important information on
the MOA.
JAPAN
WHO
Extrapolation may be
permitted if the
mechanism of action is
not unclear, the applicant
can show that a similar
pharmacological result
can
be expected for the
relevant indications,
and the mechanism of
action does not differ
among indications.
Extrapolation may be
possible if a sensitive
clinical test model has been
used that is able to detect
potential differences
between the products, that
the mechanism of action
and/or receptors are
the same, and that the
safety and immunogenicity
of the biosimilar have been
characterised and there are
no special safety issues
expected with the
extrapolated indication.
Considerations for extrapolation
• Should indications be extrapolated across disease areas where the
mechanism of action of the drug is not fully understood?
•
•
TNF-inhibitors differ in their efficacy across different inflammatory diseases
These differences are not fully understood, and have not been completely predictable –
studies of TNF-inhibitors expected to work in new indications sometimes fail to meet their
primary endpoints.1
• Should immunogenicity data gathered in a study with concomitant MTX be
used to support indications where such co-medications are not
recommended?
•
•
In some cases, a biosimilar may have its immunogenicity compared to the originator’s in a
pivotal trial using concomitant MTX, as was the case with Remsima2
Would such a study population be adequately sensitive for detecting differences in
immunogenicity?
• Is extrapolation appropriate for paediatric indications?
•
•
•
PK and PD data in paediatric populations are not available for some originator drugs, such as
infliximab3
Disease pathology is less well understood for some paediatric conditions – such as juvenile
idiopathic arthritis (JIA) – than their adult equivalents4,5
Children are known to have higher rates of certain adverse events when receiving biologic
treatment3 and may be more sensitive to immunogenic reactions than adults.6
1. Sandborn WJ, et al. Gastroenterology 2001;121:1088–1094; 2. Yoo D, et al. Ann Rheum Dis 2013. [Published online before print];
3. Remicade SPC; 4. Milojevic D. Pediatr Ann 2012;41:459;
CKD, chronic kidney disease; IV, intravenous; SC, sub-cutaneous.
5. Finnegan S, et al. Ann Rheum Dis 2011;70:1842–1850; 6. EMA/CHMP/BMWP/86289/2010.
Regulatory considerations:
Interchangeability
Interchangeable:
A therapeutically equivalent biosimilar that can be prescribed by a
physician in place of its reference product1
 EMA: Allows member countries to regulate2
 FDA: Requires additional data to classify a product as ‘interchangeable’ as
well as ‘biosimilar’3
1. Chamberlain P. Bioanalysis 2013;5:561-74; 2. EMA. Questions and answers on biosimilar medicines EMA/837805/2011;
3. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
Regulatory considerations:
Substitutability
Substitutable:
Legal status enabling substitution by the dispensing pharmacist1
 Possible with generic drugs as they are identical to the reference product
 Should not be considered acceptable with biologics2
 Pharmacovigilance data may be confounded if automatic substitution
occurs2
• Patients could receive multiple biologic/biosimilar products over the course of
therapy
• This would make it difficult to determine which product is responsible if an
adverse reaction occurs
1. Chamberlain P. Bioanalysis 2013;5:561-74; 2. Morales RE, et al. Reumatol Clin 2013;09:113-6.
Regulatory considerations: Comparison of
interchangeability and substitutability
Interchangeable:
The physician makes the
decision which product to
prescribe1
1. Chamberlain P. Bioanalysis 2013;5:561-74.
Substitutable:
The pharmacist makes the
decision which product to
dispense2
Regulatory considerations:
Pharmacovigilance
 Post-marketing surveillance is critical1,2
Approval
RCTs: Small patient numbers
mean potential risks may not
be detected prior to approval
Pharmacovigilance: Follows far greater numbers of patients
treated for much longer duration than RCTs, allowing the
detection of rarer safety signals
Figure created from 3
A risk management plan is required by FDA and EMA guidelines, which may
need to include post-marketing observational studies, inclusion of the biosimilar
in biologic registries and/or Phase IV comparative studies1,2
1. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
2. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical
and clinical issues. EMA/CHMP/BMWP/403543/2010.
3. MRHA. Pharmacovigilance - how we monitor the safety of medicines. Available at:
http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/Pharmacovigil
ance/index.htm [Accessed December 2013].
EMA, European Medicines Agency; FDA, Food and Drug Administration;
RCT, randomized controlled trial.
JOINT MEETING
Brazilian Societies of Dermatology and Rheumatology,
Brazilian Federation of Gastroenterology and IBD Brazilian
Study Group – Gediib’s Biosimilar Commission
PHARMACOVIGILANCE
 Pharmacovigilance: collecting, monitoring, and assessing
adverse effects or any other problems related to drugs,
improving patient safety
 post-marketing follow-up of a given therapeutic molecule is to
track its adverse effects quickly and accurately
 ideal system of pharmacovigilance: nomenclature system,
adequate identification of production batches, and an
operational tracking
 associations keep records of the patients who use biological
products in Brazil – biosimilars in those records
 whenever an adverse event occurs, regardless of its degree
of severity, must be easy for the professional who
prescribed it to report the adverse event and to attribute it
to the prescribed compound
Autoimmun Rev. 2015 Sep;14(9):769-73
 At PANDRH’s Seventh Conference in 2013, results of a
survey conducted by PAHO of at least two countries in
each sub-region of Latin America demonstrated that more
than half had not incorporated WHO guidelines at all, while
39 percent used only parts of the document.At the same
PANDRH meeting, the World Health Organization (WHO)
presented results of a survey of 15 drug regulatory
agencies in Latin America demonstrating substantial
differences in the approach to clinical considerations in the
regulation of biotherapeutic products.
Pan American Health Organization (PAHO) (2013). WHO Survey on Biotherapeutic Products (focus
on clinical issues). Presentation (Dr. Ivana Knezevic) at VII Conference of the Pan American
Network for Drug Regulatory Harmonization. September 5-7, 2013, Ottawa, Canada. Accessed
November 27, 2013. Available at: http://www.paho.org/hq/
index.php?option=com_docman&task=doc_download&gid=22904&Itemid=270&lang=en.
Azevedo VF, et al. GaBi Journal 2014 June 17 [Published online before print].
RECOMMENDATIONS:
The panel’s perspectives on the current status led to the following
recommendations
 :
 1) There is an urgent need for enhanced training of regulatory authorities on how
to evaluate biosimilars.
 2) A Region-wide working group should be established under the auspices of
PAHO, comprised of representatives from regulatory authorities from various Latin
American countries with expertise in biosimilars, to share their regulatory
experience and plans related to biosimilars.
 3) Each country in Latin America should establish its own working group to assist
regulatory authorities in their efforts to develop and introduce biosimilars into their
respective countries.
 4) A dedicated portion on the PRAIS website (PAHO’s Regional Platform on
Access and Innovation for Health Technologies) should be devoted to promote
discussion on biosimilars. Such topics as ongoing studies, recent approvals and
issues of concern would be the focus and would foster transparency.
 5) Countries in Latin America must enhance their efforts to
improve pharmacovigilance to include training more regulatory
staff, more public and professional awareness on the
importance of reporting adverse events and better systems to
capture and analyze data. Regulatory authorities should also
establish a process whereby the traceability of an adverse
event to a biosimilar can be determined.
 6) Products previously approved as “intended copy” drugs
should be evaluated according to regulations specific to
biosimilars. It cannot be assumed that a previously approved
biopharmaceutical is actually a biosimilar, regardless of current
clinical experience.
Regulatory pathways for
biosimilars in Latin America
Data
requirement
/policy
WHO
Chemistry,
manufacturing
and controls
documentation
Brazil
Argentina
Chile
Mexico
Venezuela
Comparability
pathway
‘”Individual
Development”
pathway
Comparative
data only
Comparative
data only
According to
developing
standards
Comparative
data only
Required as
for new drug
Required as for new
drug
Required as for new
drug
Preclinical
studies
Comparative
data only
Comparative
data only
Comparative
data with
exceptions
Comparative
data only
Comparative
data only
Required as for new
drug*
Required as for new
drug
Phase I clinical
studies
Comparative
data only
Comparative
data only
Can be waived/
may not be
comparative
Comparative
data only
Comparative
data only
Required as for new
drug
Comparative
data only
Phase II clinical
studies
Comparative
data only
Comparative
data only
Can be waived/
may not be
comparative
Comparative
data only
Comparative
data only
Comparative data
only or required as for
new drug, depending
on drug type
Comparative
data only
Phase III clinical
studies
Comparative
data only
Comparative
data only
Comparative
data with
exceptions
Comparative
data only
Comparative
data only
Comparative data
only or not required,
depending on drug
type
Required as for new
drug in most cases,
depending on the
molecule
Extrapolation of
indications
Yes
Yes
No
No
Possible once
biosimilarity
established
No
No
Azevedo VF, et al. Value in Health Regional Issues 2012;1:228–34.
*If a biosimilar product can demonstrate that its base cell culture started proliferation in a
similar manner as its originator molecule, then only comparative data will be required
Attributes Potentially Affecting the Development
of Biosimilar Policies in Five Latin American Countries
Attribute
Brazil
Argentina
Chile
Mexico
Venezuela
Large
Mid-sized
Small
Large
Mid-sized
(205M)
(42M)
(17M)
(115M)
(28M)
Interaction with international thought leaders
High
High
Medium
High
Medium
Local production capabilities
Yes
Yes
Yes
Yes
No
Safety issues with biosimilars in the past
Yes
No
Yes
Yes
No
(Wosullin)
(Kikuzubam)
Market size (population)
(hematology
product(s))
Expected differences in regulatory
requirements based on complexity of molecule
Yes
N/A
Yes
Yes
Yes
Regulatory pathway specific for biosimilars
Yes
Yes
No
Yes
No
2010
2005 / 2011
≥2012
2012
None
Year of biosimilar regulatory pathway
Azevedo VF, et al. Value in Health Regional Issues 2012;1:228–34.
Recomendaciones sobre la seguridad y
efectividad de biosimilares en LA
”Based on the evidence CTP-13 is the only Mab biosimilar marketed
in Latin America that can be considered a true biosimilar.”
“”
Intended copies available in Latin America1
Product
Manufacturer/
Commercial partner
Reference
Development
status
Countries
using the drug
Reditux
Dr. Reddy
Rituximab
Marketed
Bolivia, Chile,
India and Peru
Kikuzubam
Probiomed
Rituximab
Marketed,
withdrawn in
Mexico
Bolivia, Chile,
Mexico and
Perú
Etanar
Shanghai CP Goujian
Pharmaceutical Co
Etanercept
Marketed
Colombia,
Panama and
Ecuador
Yisaipu
Shanghai CP Goujian
Pharmaceutical Co
Etanercept
Marketed
China
Infinitam
Probiomed
Etanercept
Marketed
Mexico
Etart
Shanghai CP Goujian
Pharmaceutical
Co/Landsteiner
Etanercept
Approved, not
yet marketed
Mexico
1. Moctezuma
JF, et al.GEULAR
2013;Abstract
THU0208.
1. Castañeda-Hernández
et al. Joint
Bone Spine. 2014
Jun 20.
Regulatory considerations:
Immunogenicity
 Immunogenicity can be affected by small variations, is difficult to predict, and
can take months or even years to develop1,2
Patients (%)
Potential impact of immunogenicity
on efficacy (IFX)4
ADAb−
ADAb+
Maximum ADAb levels (AU/ml)
 A different immunogenic profile can cause differences in efficacy and safety,
and therefore threaten biosimilarity3
Potential impact of immunogenicity
on safety (IFX)4
100000
p<0.05
80000
60000
40000
20000
0
No
Yes
Infusion-related reactions
 Immunogenicity testing in biosimilars should take place in the pre-approval
clinical trials, and also form part of the post-approval risk management plan3,5
1. Schellekens H. NDT Plus 2009;2 [Suppl 1]:i27–i36.
2. Roger SD. Expert Opin Biol Ther 2010;10:1011–8.
3. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical
and clinical issues. EMA/CHMP/BMWP/403543/2010.
4. Adapted from Pascual-Salcedo D, et al. Rheumatology 2011;50:1445–52.
5. FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
ACR20/50, 20%/50% improvement in American College of Rheumatology
response criteria; ADAb, anti-drug antibody; IFX, infliximab.
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Conclusions
 Biosimilars are biopharmaceuticals that are highly similar to their
reference products, not generics
 Current analytical technologies allows for extensive characterization of
both reference product and biosimilar molecules
 Rigorous regulatory approval process: stepwise and comprehensive
comparative approach to claim biosimilarity must demonstrate a
totality of evidence with respect to the following:
• Physiochemical molecular characteristics and biologic activity
• Pharmacokinetics, as well as clinical safety and efficacy
 Rigorous pharmacovigilance programs must be established to monitor
safety and efficacy issues during the postapproval period
 Biosimilars follow this strict criteria to demonstrate comparable safety
and efficacy to the reference product