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8.11 Biosimilars 185
Table 8.5 EU Biosimilar guidelines as developed and published by the European
Medicines Agency.
Overarching guidelines
Similar biological medicinal products
Similar biological medicinal products containing biotechnology-derived proteins as active
substance: non-clinical and clinical issues
Similar biological medicinal products containing biotechnology-derived proteins as active
substance: quality issues
Product class-specific guidelines:
Biosimilar medicinal products containing
recombinant granulocyte-colony
stimulating factor (Annex to guideline on
similar biological medicinal products
containing biotechnology-derived proteins
as active substance: non-clinical and
clinical issues)
Similar medicinal products containing
somatropin (Annex to guideline on similar
biological medicinal products containing
biotechnology-derived proteins as active
substance: non-clinical and clinical issues)
Non-clinical and clinical development of
similar biological medicinal products
containing recombinant human insulin
and insulin analogues
Similar biological medicinal products
containing interferon beta
Similar biological medicinal products
containing monoclonal antibodies:
non-clinical and clinical issues
Similar biological medicinal products
containing recombinant erythropoietins
Similar biological medicinal products
containing recombinant
follicle-stimulating hormone
Non-clinical and clinical development of
similar biological medicinal products
containing low-molecular-weight heparins
product, to which it claims similarity. The application dossier (relative to the one
for the original reference product) must contain a full quality module as well as
reduced clinical and nonclinical data modules, and it must demonstrate that both
products are comparable, both therapeutically and from a quality standpoint. As of
mid-2021, European regulations and guidelines have facilitated regulatory approval
of 76 biosimilar products (Table 8.6).
8.11.2 US Regulations
An abbreviated approval pathway for biosimilars was created in the US by the
Biologics Price Competition and Innovation Act (BPCI Act) of 2009. Subsequently,
the FDA has developed and published a number of biosimilar guidelines (Table 8.7).
Comparative data between the putative biosimilar and the reference product is
required and the guidelines emphasize that the FDA takes a risk-based ‘totality of
the evidence’ based approach. As of mid-2021, 30 biosimilar products had gained
marketing approval in the US (Table 8.8).
186 8 Variations to the Drug Authorisation Process
Table 8.6 Biosimilar products approved in the EU by mid-2021.
Product type Biosimilar (tradename) Year approved Reference product
hGH-based Omnitrope 2006 Genotropin
Valtro pin 2006 (withdrawn 2012) Humatrope
EPO-based Binocrit 2007 Eprex/Erypo
Epoetin alfa hexal 2007 Eprex/Erypo
Abseamed 2007 Eprex/Erypo
Retacrit 2007 Eprex/Erypo
Silapo 2007 Eprex/Erypo
G-CSF-based Ratiograstim 2008 Neupogen
Filgrastim ratiopharm 2008 (withdrawn 2011) Neupogen
Biograstim 2008 (withdrawn 2015) Neupogen
Tevagrasti m 2008 Neupogen
Zarzio 2009 Neupogen
Filgrastim hexal 2009 Neupogen
Nivestim 2010 Neupogen
Grastol 2013 Neupogen
Accol 2014 Neupogen
Fulphila 2018 Neulasta
Pelmeg 2018 Neulasta
Pelgraz 2018 Neulasta
Udenyca 2018 Neulasta
Ziextenzo 2018 Neulasta
Grasustek 2019 Neulasta
Cegla 2019 Neulasta
Nyvepria 2020 Neulasta
FSH-based Ovaleap 2013 Gonal F
Bemfola 2014 Gonal F
Insulin glargine
based
Abasaglar 2014 Lantus
Lusduna 2017 Lantus
Semglee 2018 Lantus
Insulin lispro
based
Insulin lispro Sano 2017 Humalog
Liumjev 2020 Humalog
Insulin Aspart
based
Insulin aspart Sano 2020 NovoRapid
Kirsty 2021 NovoRapid
(Continued)
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8.11 Biosimilars 187
Table 8.6 (Continued)
Product type Biosimilar (tradename) Year approved Reference product
Mab:
Iniximab-based
Inectra 2013 Remicade
Remsima 2014 Remicade
Flixabi 2016 Remicade
Zessly 2018 Remicade
Mab: Adalimumab-
based
Amgevita 2017 Humira
Solymbic 2017 Humira
Cyltezo 2017 Humira
Halimatoz 2018 Humira
Heya 2018 Humira
Hulio 2018 Humira
Hyrimoz 2018 Humira
Imraldi 2017 Humira
Idacio 2019 Humira
Kromeya 2019 Humira
Amsparity 2020 Humira
Yuyma 2021 Humira
Mab:
Rituximab-based
Blitzima 2017 MabThera
Truxima 2017 MabThera
Ritemvia 2017 MabThera
Rituzena 2017 MabThera
Rixathon 2017 MabThera
Riximyo 2017 MabThera
Ruxience 2020 MabThera
Mab:
Trastuzumab-based
Ontruzant 2017 Herceptin
Ogivri 2017 Herceptin
Herzuma 2018 Herceptin
Kanjinti 2018 Herceptin
Trazimera 2018 Herceptin
Zercepac 2020 Herceptin
Mab: Bevacizumab
based
Mvasi 2018 Avastin
Zirabev 2019 Avastin
Aybintio 2020 Avastin
Equidacent 2020 Avastin
Onbevzi 2021 Avastin
Etanercept-based Benepali 2016 Enbrel
Erelzi 2017 Enbrel
Nepexto 2020 Enbrel
188 8 Variations to the Drug Authorisation Process
Table 8.6 (Continued)
Product type Biosimilar (tradename) Year approved Reference product
Teriparatide-based Movymia 2017 Forsteo
Ter rosa 2017 Forsteo
Livogiva 2020 Forsteo
Qutavina 2020 Withdrawn 2020 Forsteo
Enoxaparin-based Inhixa 2016 Clexane
Thorinane 2016, withdrawn 2019 Clexane
hGH = Human Growth Hormone; EPO = Erythropoietin; G-CSF = Granulocyte Colony
Stimulating Factor; FSH = Follicle Stimulating Hormone; Mab = Monoclonal antibody.
Table 8.7 US biosimilar guidelines and draft guidelines developed or in development by
October 2021.
Guideline Status
Reference Product Exclusivity for Biological Products Filed
Under; Draft Guidance for Industry
Published in 2014
Quality Considerations in Demonstrating Biosimilarity of a
Therapeutic Protein Product to a Reference Product; Guidance for
Industry
Published in 2015
Scientic Considerations in Demonstrating Biosimilarity to a
Reference Product; Guidance for Industry
Published in 2015
Clinical Pharmacology Data to Support a Demonstration of
Biosimilarity to a Reference Product: Guidance for Industry
Published in 2016
Labelling for Biosimilar Products; Guidance for Industry Published in 2018
Considerations in Demonstrating Interchangeability With a
Reference Product; Guidance for Industry
Published in 2019
Development of Therapeutic Protein Biosimilars: Comparative
Analytical Assessment and Other Quality-Related
Considerations; Draft Guidance for Industry
Published in 2019
Biosimilars and Interchangeable Biosimilars: Licensure for Fewer
Than All Conditions of Use for Which the Reference Product Has
Been Licensed; Draft Guidance for Industry
Published in 2020
Biosimilarity and Interchangeability: Additional Draft Q&As on
Biosimilar Development and the BPCI Act; Draft Guidance for
Industry
Published in 2020
New and Revised Draft Q&As on Biosimilar Development and the
BPCI Act (Revision 3); Draft Guidance for Industry
Published in 2021
Questions and Answers on Biosimilar Development and the BPCI
Act; Guidance for Industry
Published in 2021
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8.12 Reference Drug Exclusivity 189
Table 8.8 Biosimilar products approved in the US by mid-2021.
Product type Biosimilar (tradename) Year approved Reference product
EPO-based Retacrit 2018 Epogen/procrit
G-CSF-based Zarxio 2015 Neupogen
Nivestym 2018 Neupogen
PEGylated G-CSF based Fulphila 2018 Neulasta
Udenyca 2018 Neulasta
Ziextenzo 2019 Neulasta
Nyvepria 2020 Neulasta
Insulin glargine based Semglee 2021 Lantus
Mab: Iniximab-based Inectra 2016 Remicade
Renexis 2017 Remicade
Ixi 2017 Remicade
Avsola 2019 Remicade
Mab: Adalimumab-based Amjevita 2016 Humira
Cyltezo 2017 Humira
Hyrimoz 2018 Humira
Hadlima 2019 Humira
Abrilada 2019 Humira
Hulio 2020 Humira
Mab: Rituximab-based Truxima 2018 Rituxan
Ruxience 2019 Rituxan
Riabni 2020 Rituxan
Mab: Trastuzumab-based Ogivri 2017 Herceptin
Herzuma 2018 Herceptin
Kanjinti 2019 Herceptin
Ontruzant 2019 Herceptin
Trazimera 2019 Herceptin
Mab: Bevacizumab based Mvasi 2017 Avastin
Zirabev 2019 Avastin
Etanercept-based Erelzi 2016 Enbrel
Eticovo 2019 Enbrel
EPO = Erythropoietin; G-CSF = Granulocyte Colony Stimulating Factor; Mab = Monoclonal
antibody.
8.12 Reference Drug Exclusivity
To encourage and reward the originators of new drugs the regulations contain
restrictions to prevent the entry of generic copies onto the market for set time
periods.
190 8 Variations to the Drug Authorisation Process
In Europe, a manufacturer of a human medicine may not submit an application
that relies on a reference drug (unless granted a right of reference by the originator)
for a periodof eight years afterthe initial approval of the reference drug. Such a prod-
uct may not be authorised for a further two years giving an eective total of 10 years
of data exclusivity. The period of exclusivity for a human medicine may be extended
to 11 years if a new therapeutic indication with signicant benet over existing ther-
apies was approved within the rst eight years of the data exclusivity window. Sim-
ilarly, a minimum of 10 years of data exclusivity applies to veterinary medicines for
cattle, sheep for meat production, pigs, chickens, dogs and cats, whereas a period
of 14 years applies to new active substance antimicrobial medicines and medicines
for other species except bees where the exclusivity period is 18 years. The period of
protection may be extended by between one and four years by adding new species
subject to a limit of 18 years of maximum protection.
In the US, a manufacturer may not submit an application for a generic drug
that relies on data from an approved submission for a period of ve years after
the reference product was authorised, unless the ‘owner’ of the original data
has granted a right of reference. In the case of biopharmaceuticals, the period of
protection aorded to a reference product is 12 years. The FDA may not approve
an application that relies on data submitted as a supplement (e.g. new therapeutic
indication) to an authorised drug for a period of three years after approval of the
supplement. These exclusivity periods will be extended by six months if the
reference submissions contain paediatric data.
Reference products may also benet from patent protection. As a signicant
amount of the standard protection period of 20 years may have elapsed before the
developer can market a product, the periods of patent protection can be extended
to compensate for this (see Table 8.9). The FDA cannot grant approval to a generic
product if the drug is still under patent protection. This is why US applications must
include information on patents, and in the case of abbreviated applications, certi-
cation as to patent status, i.e. expiry date, or claims of noninfringement or invalidity.
The protection periods available to originators are summarised in Table 8.9 and
Figure 8.2.
Table 8.9 Protection intervals allowed to developers of innovator products (years).
Type of protection EU US
Patent 20 20
Patent extension
(maximum)
15 from rst marketing
approval
14 from marketing approval
Pediatric applications +0.5 (patent extension) +0.5
Data exclusivity 10 (human)
10, 14 or 18 (veterinary)
5 (drug), 12 (biopharmaceutical)
Orphan drug 10 7
New therapeutic
indication
+1 (human) to +4
(veterinary)
3 from approval of indication
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8.13 Other Authorisation Procedures 191
Development Scenario (Human medicine)
● New pharmaceutical form approved six years after approval of the original product.
● A paediatric application approved for the new pharmaceutical form seven years after
approval of the original product.
● New dosage regimen for the original product approved eight years after approval of
the original product.
EU Relevant Exclusivity
● The generic manufacturer may not place a copy of either the original product or the
new pharmaceutical form on the market for a period of 11years after the approval
of the original product (i.e. 10 years + 1 year added to the global market exclusivity
period, because of new indications).
US Relevant Exclusivity
● The generic manufacturer may not submit an ANDA for the original product until
5 years after approval of the original form.
● The generic manufacturer may not submit an ANDA for the new pharmaceutical
form until 11.5 years after approval of the original product (i.e. 5years from the date
of approval of the new form +0.5 years for the paediatric application).
● The new dosage regimen may not be approved until 11 years after the original product
was approved (i.e. 8+ 3).
Figure 8.2 Illustration of the application of exclusivity periods according to EU and US
regulations.
8.13 Other Authorisation Procedures
There are a number of other scenarios where medicinal products may be brought
to market exempt from the requirement to submit applications supported by full
preclinical and clinical data.
8.13.1 Well-Established Medical Use Products
The EU will accept applications without supporting preclinical and clinical data,
if it can be demonstrated that the active substances have been in well-established
medical use in the community for at least 10 years, with recognised ecacy and
an acceptable level of safety. This route would be appropriate for many common
over the counter (OTC) products. Safety and ecacy are supported by providing
copies of published scientic literature as part of the submission, i.e. the submis-
sion relies on safety and ecacy data available in the public domain as opposed to
condential data from authorised applications that is the corner-stone of generic
applications.
8.13.2 Combination Products
An EU application for a combination product that contains previously authorised
active substances must be supported by appropriate safety and ecacy data for the
combination. However, there is no need to submit data on the safety and ecacy of
192 8 Variations to the Drug Authorisation Process
the components individually. The combination product is considered a unique prod-
uct distinct from the authorisations granted to the individual ingredients and will
thus have a separate exclusivity clock running from the date when the combination
was authorised.
8.13.3 Homeopathic Medicines
Homeopathic medicines mayavailof a simplied registration procedure if they full
the following criteria:
● They are administered orally or externally (via European Pharmacopoeial route
in the case of veterinary products),
● No specic therapeutic indication appears on the labelling and
● There is a sucient degree of dilution to guarantee the safety of the medicinal
product (not more than one in 10,000 of the mother tincture or 1/100th of the
small dose requiring a medical prescription in allopathic medicinal product).
A dossier that focuses on quality (manufacture, control, stability) and labelling of
the product must be submitted in support of the application.
8.13.4 Traditional Herbal Medicines
Traditional herbal medicines may also avail of a simplied registration procedure if
they full the following criteria:
● They have indications exclusively appropriate to traditional herbal medicinal
products, which by virtue of their composition and purpose, are intended and
designed for use without the supervision of a medical practitioner for diagnostic
purposes or for prescription or monitoring of treatment,
● They are exclusively for administration in accordance with a specied strength
and posology,
● They are an oral, external and/or inhalation preparation,
● They must have been in traditional use for at least 30 years, 15 years of which must
be in the EU and
● Traditional use data is available that supports the precepts that they are not harm-
ful under the conditions of useand that ecacy is plausible based on longstanding
use and experience.
The approach is quite similar to that for a well-established medical product in
that the applicantmust submit bibliographic data supporting the safety, ecacy, and
duration of the traditional use of the herbal remedy (See Table 8.10).
All other homeopathic and herbal medicines that do not qualify for simplied
registration procedures will have to go through the standard authorisation pro-
cedure with supporting technical dossiers. The Committee for Herbal Medicinal
Products has been charged with preparing monographs on herbal products so as to
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8.14 Chapter Review 193
Table 8.10 Overview of study requirements and data presentation for different types of
application.
Application type Labelling Quality Safety Efficacy
Standard
authorisation
Yes (SPC) Yes (CMC &
Stability)
Yes (Pre-clinical
& Clinical data)
Yes (Clinical
data)
Generic
authorisation
Yes (SPC) Yes (CMC &
stability)
No (Reference
dossier)
No (Reference
dossier)
Well-established
use authorisation
Yes (SPC) Yes (CMC &
stability)
No (Published
literature)
No (Published
literature)
Homeopathic
registration
Yes Yes (Manufacture,
control & stability)
No (Sucient
dilution)
No (No
therapeutic
indications)
Traditional Herbal
Product
Registration
Yes (SPC) Yes ( Manufacture,
control & stability)
No (Published
literature)
No (Published
literature)
further facilitate the registration of traditional and well-established use of herbal
products.
8.13.5 US Regulation of OTC Drugs
OTC drugs are not required to go through the new drug application procedures that
apply to prescription only (‘Rx’) drugs in the US. Instead, they can be marketed on
the principle that all the active ingredients have been deemed by the FDA to be
‘Generally Recognised as Safe and Eective’ (GRASE). To be available without pre-
scription, OTC drugs must have a wide safety margin, which is usually underpinned
by a long history of safe use. As many of the drugs came on the market before there
was a requirement to demonstrate safety and ecacy, the FDA undertook a review
of OTC products in 1972. Rather than look at what was then in excess of 300,000
individual products, expertpanels reviewed them by active ingredient and therapeu-
tic class. These reviews were based on the publicly available scientic and medical
literature on safety and ecacy. Following public consultation, these reviews were
condensed into monographs, which dene the basic formulation, use, and labelling
conditions that a manufacturer must follow. Manufacturers may submit an amend-
ment to a monograph to switch a more recently developed drug to OTC status.
8.14 Chapter Review
Depending on the circumstances, manufacturers may be able to avail of variations
from the standard marketing authorisation procedures. These include incentives
such as the Orphan drug, paediatric use, and minor species minor use provisions,
194 8 Variations to the Drug Authorisation Process
which are intended to encourage greater availability of drugs for treatment groups
that might not be nancially attractive. To speed up access to drugs that represent a
signicant advance in the treatment of serious/life-threatening diseases, there is the
possibility to fast-track the approval and /or make them available on compassionate
grounds prior to approval. Manufacturers that wish to introduce generic copies of
innovator products, are not required to repeat nonclinical and clinical studies but
can rely on the original innovator’s data. The innovator may use a combination of
patent and data protection to exploit the drug before generic copies can come on
the market. The regulatory authorities must be informed of all changes relating to
an approved product. This can range from the most minor change, which does not
require prior approval to signicant changes that must follow essentially the same
approval process as the original product. The specic requirements dier somewhat
between Europe and the US.
8.15 Further Reading
European Regulations and Guidance
Consolidated Human Medicines Directive 2001/83/EC, Title III
Consolidated Orphan Drug Regulations (EC) No. 141/2000 and (EC) No. 847/2000
Consolidated Paediatric Use Regulation (EC) No. 1901/2006
Supplementary Protection (Patent) Regulation (EC) No. 469/2009
Consolidated Variations Regulation (EC) No. 1234/2008
The Rules Governing Medicinal Products in the European Union, Volume 2, Notice to
Applicants, Medicinal Products for Human Use
The Rules Governing Medicinal Products in the European Union, Volume 6, Notice to
Applicants, Veterinary Medicinal Products
https://ec.europa.eu/health/documents/eudralex_en
Veterinary Medicines Regulation (EU) 2019/6, Chapters II & III
https://eur-lex.europa.eu
Biosimilar guidance
https://www.ema.europa.eu/en/human-regulatory/research-development/scientic-
guidelines/multidisciplinary/multidisciplinary-biosimilar
US Code of Federal Regulations
21 CFR Part 314
21 CFR Part 514
21 CFR Part 601
https://www.ecfr.gov
US Food, Drug & Cosmetic Act
Chapter 5, Sub chapter B, F
Biosimilar regulatory information, US: https://www.fda.gov/drugs/therapeutic-
biologics-applications-bla/biosimilars
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