1. health and fitness
2. drugs

Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
ORIGINAL ARTICLE
How to select a biosimilar
Niels Boone,1 Hugo van der Kuy,1 Mike Scott,2 Jill Mairs,2 Irene Krämer,3
Arnold Vulto,4 Rob Janknegt1
1
Department of Clinical
Pharmacy and Toxicology,
Orbis Medical Center,
Sittard-Geleen, The
Netherlands
2
Department of Clinical
Pharmacy, Antrim Area
Hospital, Antrim, UK
3
University Medical Center,
Johannes Gutenberg University,
Mainz, Germany
4
Department of Clinical
Pharmacy and Toxicology,
Erasmus Medical Center,
Rotterdam, The Netherlands
Correspondence to
Niels Boone,
Orbis Medical Center,
Department of Clinical
Pharmacy and Toxicology, PO
Box 5500, Sittard-Geleen NL
6130 MB, The Netherlands;
[email protected]
Received 1 August 2013
Accepted 6 August 2013
Published Online First
28 August 2013
To cite: Boone N, van der
Kuy H, Scott M, et al. Eur J
Hosp Pharm 2013;20:
275–286.
ABSTRACT
In the past few years biosimilars have penetrated the
market following the expiry of patents of originator
variants. This offers the opportunity to apply high-tech
protein products at a lower cost. In contrast to
small-molecule generics, clinicians and pharmacists have
found it difficult to judge the efficacy and safety profiles
of complex protein products. In recent years, the
European Medicines Agency (EMA) has gained
knowledge on assessing comparability between
biosimilars and originator products in scientific and
legal areas. This article provides an overview of an
extensive set of 31 previously drawn biosimilar selection
criteria and describes how several of these criteria are
covered by EMA regulations and guidelines. A panel of
experts (authors) reviewed the criteria and produced a
shortlist of 10 criteria relevant for clinicians and
pharmacists.
INTRODUCTION
Selection of biosimilars in hospitals is a relatively
new issue. Biosimilars have also been referred to as
follow-on protein products, follow-on biologicals,
bio-therapeutic similars, similar biological medicinal products, similar bio-therapeutic products,
etc. Patents of several expensive biopharmaceutical
products have expired or are due to expire shortly.
This is important due to the continuously increasing costs in healthcare and the numerous oncology
drugs under development. The introduction of biosimilars was expected to reduce the costs of these
medicines due to the enhancement of competition
in biological medicine markets. Although costs have
reduced, they have not decreased to the same
extent as occurred in the generic small-molecule
market.1 Costs of biosimilars are about 15–30%
less than the originator prices in the European
Union (EU) and the USA.2 Depending on the type
of reimbursement system, cost reductions of medicines could improve patient access to biotechnological products in some European countries (eg,
The Netherlands).
In contrast to generic small-molecule medicines,
biosimilars are not identical to their reference
product. New biosimilars have to be evaluated for
inclusion into a hospital formulary. In this evaluation of biosimilars, it is necessary to have a complete and rational set of criteria to determine
clinically and non-clinically relevant differences
between biosimilars and to compare these to the
reference product.3 4 See box 1 for an explanation
of terminology.
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
A different generic approach
Non-protein drugs are typically organic molecules
of low molecular mass and well defined molecular
structure. Because the molecular structure of such a
small-molecule drug can be fully analytically characterised, it is fairly easy for a generic drug manufacturer to produce a bio-equivalent medicinal
product with the same drug usage form containing
the same active ingredient as the innovator’s drug
product.
A protein product is a heterogeneous mixture of
large molecules based on a sequence of amino acids
folded in secondary and tertiary three-dimensional
structures, which undergo post-translational folding
processes to ultimately fold into a complex spatial
structure. Post-translational modification is a function of host cells, which are not identical for the
biosimilar and the originator medicinal product.
This complex process is difficult to reproduce even
in the production process of the originator drug. A
full chemical characterisation of the product resulting from this process is a challenge using multiple
analytical tools. However, it is not easy to decide
which battery of chemical tests should be performed to counter certain clinical risks.5
In the hypothetical situation of using the same
recombinant genetic construct, type of host cell,
culture conditions and downstream processing like
purification techniques, formulation and packaging
there is no guarantee of bioequivalence or ability to
substitute for the reference products. Companies use
a unique master cell bank, which remains under
patent, and proprietary techniques that may affect
the efficacy and safety of a product.6 However, the
concept of developing a biosimilar medicinal product
is to reverse engineer the reference product whereby
companies use their own state-of-the art process
and production facilities to achieve the same
quality profile as the originator medicinal product
(J Windisch, personal communication).
An important question is how the biosimilar
product variation compares with the originator
product batch variation. Different immunogenicity,
differences in pharmacokinetic behaviour and distribution can be clinical consequences caused by
variation in the tertiary structures of the protein
drug products, for example caused by differences
in post-translational modification.7
There are a number of issues that will make
selection of biosimilars much more complicated
and specific than the selection of generic drugs.
Given the complexity of producing and regulating
biological medicinal products, a checklist must be
established, including all aspects that could affect
the quality, efficacy and safety of biosimilars.
275
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
indication. In some cases the industry does not fully adhere
to these programmes.9
Companies that develop biosimilar medicinal products have a
quadruple mission to fulfil in comparison to the manufacturers of
the originator product. They have to bring a complex product to
the market that must be similar in numerous aspects to its originator counterpart but with lower acquisition costs and must meet
US Food and Drug Administration (FDA) and European
Medicines Agency (EMA) biosimilar regulatory standards that
become higher and more clearly defined as they move away from
the generic paradigm. During the latter half of 2012, Samsung and
Teva-Lonza who were developing a rituximab biosimilar (the
patent is due to expire in 2013) struggled with their research programmes due to regulatory issues and cost aspects.10
So far, the market uptake of biosimilar products has been relatively low in the EU. Market penetration is the lowest (below 5%;
biosimilars vs total of biosimilars and reference products) in The
Netherlands, Belgium, Norway and Austria for biosimilars of the
above-mentioned reference products.11 However, the combined
market share of biosimilar versions of the reference products
Eprex, Genotropin and Neupogen have grown in recent years
from 0.33% in 2007 to 15.52% in 2010.11 In fact, biosimilars
may lead to lower prices for the originator products, without
obtaining a relevant market share. This is advantageous from a
societal aspect, but does not encourage other companies to invest
in the development of biosimilars.
Box 1 Biosimilar definitions
European Medicines Agency
A biosimilar medicine is a medicine, which is similar to a
biological medicine that has already been authorised (the
‘biological reference medicine’). The active substance of a
biosimilar medicine is similar to the one of the biological
reference medicine. Biosimilar and biological reference
medicines are used in general at the same dose to treat the
same disease.
A biological medicine is a medicine whose active substance is
made by or derived from a living organism.
(London, 22 October 2008, Doc Ref EMEA/74562/2006 Rev 1).
Food and Drug Administration
A biosimilar is a biological product that is highly similar to a
US-licensed reference biological product notwithstanding minor
differences in clinically inactive components, and for which
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.
Biological products can include a wide range of products
including vaccines, blood and blood components, allergenics,
somatic cells, gene therapy, tissues, and proteins. Unlike most
traditional, small-molecule prescription drugs that are made
through chemical processes, biological products are generally
made from human and/or animal materials. Biological products
are usually larger than and have a more complex structure than
small-molecule prescription drugs. Such products may be
manufactured through biotechnology, derived from natural
sources, or, in some cases, produced synthetically (http://www.
fda.gov 11 March 2011).
Substitution and therapeutic interchange
Most clinicians and pharmacists are uncertain about the
evaluation of a biosimilar medicinal product due to the following factors:
▸ The complex nature of a biological medicinal product and its
production process. The whole concept of identity is not
applicable to biological medicines, either to the different
batches of the originator medicinal products or to the original products before and after changes in the manufacturing
process.
▸ Comparability trials could be conducted with different efficacy endpoints than those used in the initial trials with the
originator product.8 The use of different endpoints makes it
complicated for prescribing doctors or pharmacists who lack
experience with the biosimilarity of medicines. Clinicians
and pharmacists must realise that the aim of a biosimilar
development programme and clinical trials is not to establish
benefit; the aim is to prove biosimilarity.
▸ Similarity and safety are studied in a specific patient population which makes it difficult to extrapolate the risks and benefits to individual patients in clinical practice. Due to the
nature of biosimilar comparability trials a limited patient
population is often studied in terms of indication, comorbidities, comedication, age and gender.
▸ Important clinical information regarding long-term effects
must be collected during the post-marketing phase according
to the risk management programmes, which have to be
implemented by the manufacturer to collect information
about the efficacy and safety of approved biosimilar medicinal products that do not always comply with the authorised
276
The differences between small-molecule medicines and biosimilar products have prompted questions relating to the substitution of biosimilars. It is important to note that selection criteria
can be different for both types of medicinal products.
Substitution means that a pharmacist can substitute the originator product for a biosimilar without information from the prescribing physician. In this case both products are designated as
interchangeable, which means that they can be alternated or
switched. The Biologics Price Competition and Innovation Act,
Section 351k, part of the American Affordable Care Act (2010),
created an abbreviated FDA legislation pathway for similar
biological products to become interchangeable with an
FDA-licensed reference product. A designation of ‘interchangeable’ by the FDA is a stepwise process after proving biosimilarity
but will be hardly impossible in a scientific way. Currently the
FDA is considering which clinical and non-clinical information
is necessary to delineate a biological as interchangeable.12 13 In
the case of biosimilar medicinal products it is worth mentioning
that the granting of approval does not mean that the biosimilar
product can be automatically substituted for the reference
product and vice versa. EMA does not make recommendations
about interchangeability between a biosimilar medicinal product
and its reference product and leaves this question to be
answered based on to the judgement of the patient’s clinician
and the pharmacist.14 Most clinicians and hospital pharmacists
lack the knowledge to make a sound clinical judgement of all
aspects of biosimilars. Several EU countries, such as France,
Spain, Italy, Germany, The Netherlands, the UK and Sweden,
have established legislative measures that forbid the automatic
substitution of these products.15
However, the Dutch Ministry of Health has allowed health
insurers to include generics in their preference policies. In this
Dutch example insurers can choose to reimburse only a certain
label of a generic medicine based on its costs. The physician can
bypass this preference policy by specifying on the prescription
that the patient has to use the originator product for a medical
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
reason. In the same way, insurers in The Netherlands can now
select a biosimilar for preferred reimbursement in the case of
patients who are biological naïve. Some authors state that only a
doctor can decide whether or not to switch a patient’s treatment
to a biosimilar product.16 But in daily clinical practice the individual physician will not have access to all the information that is
mandatory to make a sound decision. According to the data available, the selection process of a biosimilar as a preferred product
by healthcare insurers seems to be based only on cost. A full set
of selection criteria used by insurance companies is not available.
To date, 13 biosimilars have been approved in Europe, covering
only three reference products (Filgrastim, Epoetin, Genotropin).
See table 1 for a list of these biosimilars. Some of these products
are identical to each other because they are based on the same
dossier and are comarketed. It is important to realise that the
number of biosimilars and regulatory requirements will increase
rapidly due to the expiration of patents, therefore constant review
and assessment of the checklist is necessary.
Due to the complexity of the process, it is not realistic for
individual hospital pharmacists and clinicians to have enough
time and knowledge to make a sound judgement of the properties of individual biosimilars. Therefore, it would be useful to
determine a standard set of criteria for the judgement of biosimilars. Based on an extensive literature search, a panel of
experts would establish the properties of the various biosimilars
(and reference product). Individual hospital pharmacists (and
clinicians) may assign a relative weight to each selection criterion, thereby making a personal but transparent and rational
drug selection possible. The methodology is similar to that of
the System of Objectified Judgement Analysis (SOJA).17 To
ensure an adequate selection of biosimilars the authors used an
evaluation checklist based on an established checklist proposed
by Irene Krämer4 and the SOJA and InforMatrix selection criteria.17 18 The full list of selection criteria is shown in table 2.
STEPSelect, which is a comprehensive quality, safety and efficacy based system, was proposed for the establishment of prequalification criteria.19 Then, all selection criteria were critically
judged by an extensive panel of experts to distinguish those criteria that are adequately covered by EMA. Due to changes in
the EMA regulations and more experience since the publication
of Irene Krämer`s checklist, some of the questions are superfluous today. The remaining selection criteria are listed in table 3.
Table 1 Biosimilars authorised by EMA
Name
Active substance
Status
Abseamed
Binocrit
Biograstim
Epoetin α Hexal
Filgrastim Hexal
Filgrastim Ratiopharm
Nivestim
Omnitrope
Ratiograstim
Retacrit
Silapo
Tevagrastim
Valtropin
Zarzio
Epoetin α
Epoetin α
Filgrastim
Epoetin α
Filgrastim
Filgrastim
Filgrastim
Somatropin
Filgrastim
Epoetin ζ
Epoetin ζ
Filgrastim
Somatropin
Filgrastim
Authorised
Authorised
Authorised
Authorised
Authorised
Withdrawn
Authorised
Authorised (public health alert)
Authorised
Authorised
Authorised
Authorised
Authorised (public health alert)
Authorised
EMA, European Medicines Agency.
DISCUSSION
Pre-qualification criteria
Prior to the establishment of biosimilar selection criteria the following aspects relating to pharmaceutical licensing, reliability of
supply, facilitation of a 24 h contact service with a medical division of the company to report adverse events, financial and
insurance criteria, as well as public and product liability play a
role. These aspects are supplemented with product-specific medication safety criteria in STEPSelect and together form important
pre-qualification criteria to be used as a prerequisite.19
A: Production process/manufacturer
Risk management and quality assurance are integral parts of an
effective pharmaceutical quality assurance system that can provide
a proactive approach to identify, scientifically evaluate and control
potential risks in quality. Such a system facilitates continuous
improvement in process, performance and product quality
throughout the product lifecycle20 and can also be applied to biotechnological products. The authors consider this the responsibility
of EMA.
The International Conference on Harmonisation (ICH) of
Technical Requirements for Registration of Pharmaceuticals for
Human Use guidelines harmonise legislation between Europe,
Japan and the USA. A medicine that complies with ICH guidelines can be marketed in Europe, Japan and the USA. The guidelines are based on good manufacturing practice (GMP) rules.
Quality by design (QbD) is a part of the ICH guidelines and,
although not mandatory, if a manufacturer complies with QbD
this indicates the medicinal product is of high quality. QbD
models can enhance scientific understanding and possibly
predict the behaviour of a system under a set of conditions.
These models indicate product quality and that the whole
process is controlled, thus the risks associated with processes are
decreased. Also, there is continuous process verification and
improvement which minimises the risks associated with manufacturing failures and product recalls. QbD is explained in ICH
Q8, 9, 10 and 11.21–24 In the case of biosimilars, EMA asks for
compliance with the ICH guidelines.
Specifications for quality control are covered by the ICH
Q6B ‘Guidance on test procedures and acceptance criteria for
biotechnological/biological products’ guideline.25 A rationale
has to be provided for the use of certain product-specific
acceptance criteria based on data obtained from batches used
during clinical and non-clinical tests supported by the applicant’s experience of the biosimilar product and testing of the
reference product.
A1: Are all biosimilars approved in Europe produced under GMP
conditions?
It is important to track down and check how EMA deals with
the quality status of active pharmaceutical ingredients (APIs),
excipients and finished products. This is relevant in when the
manufacturing process is undertaken by a third party. Directive
2011/62/EU lays down considerations separately for APIs and
finished medicinal products.26
Pharmaceutical companies in Europe are obliged to establish
and implement GMP. When the marketing authorisation holder
(MAH) asks for approval of a medicinal product, it must
comply with GMP. When an applicant brings a new medicinal
product to the market, EMA has to inspect the manufacturer
for GMP and good clinical practice (GCP).27 28
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
277
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
Table 2 Full set of potential selection criteria
A
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
A14
A15
A16
A17
B
B1
B2
B3
C
C1
D
D1
E
E1
E2
E3
F
F1
F2
F3
F4
F5
G
G1
G2
Production process/manufacturer
Are all biosimilars approved in Europe produced under GMP conditions?
Is the exact production site of API and final product always known to EMA?
Have all production facilities of API and final product been checked by EMA or other authorities?
Are all recalls reported to EMA?
Is the manufacturer experienced in the production of biopharmaceuticals?
Which national authorities are responsible for inspecting the manufacturing site?
How long has the biopharmaceutical been on the market?
How extensive is the clinical experience with each individual biosimilar? Expressed as the number of patient-days worldwide
Does the manufacturer guarantee active information about major changes of the manufacturing process?
Is the reference medicinal product authorised in the European Community?
How has it been validated that the production of the API and final product is always performed under the same conditions?
Has EMA checked quality control systems of the producers of API and final product?
Are data concerning batch reproducibility (inter-batch and intra-batch variability) available at EMA before and after approval?
Are specifications of quality control of the marketing authorisation holder (MAH)/manufacturer known to EMA and assessed by EMA?
Is it taken into consideration whether materials of animal origin or potentially allergenic materials are used during the production or formulation?
Does EMA take into consideration where clinical studies were performed or is only the quality of the study an item of discussion?
How is batch consistency ensured by the manufacturer and/or by third party?
Product specifications
Are there any differences in isoform pattern in comparison to the reference product or other biosimilars?
Are there any differences in drug formulation and administration in comparison to the reference product or other biosimilars?
What is the number of registered indications for the biopharmaceutical/biosimilar?
Reliability of supply
Does the supplier reliably guarantee the supply of the biosimilar over a long time period?
Good handling practice
Is the biosimiliar delivered according to good storage (GSP) and distribution practice (GDP)?
Clinical efficacy
Is the clinical development programme consistent with the current regulatory requirement?
Which clinical trials in which patient populations with which designs, endpoints and results were performed?
Are there different results in comparison to the reference product?
Clinical safety and tolerability
Which (serious and mild) adverse events and in which frequency were they reported in clinical trials with the biopharmaceutical?
Are there any contraindications, precautions or warnings which are different compared with the reference product?
Is immunogenicity, as far as known, caused by a homogeneous type of antibody or is there a high intra-individual or inter-individual variability? Is there a difference
between biosimilar products regarding drug antibody homogenicity?
Are there differences in the incidence and severity of drug interactions
Are there differences in the incidence of local reactions?
Pharmacovigilance
Does the MAH have a 24 h phone number equipped with adequate personnel to report adverse events?
How is pharmacovigilance controlled?
EMA, European Medicines Agency; GMP, good manufacturing practice.
Table 3 Final set of selection criteria for evaluation of biosimilars
A
1
2
3
B
4
5
E
6
F
7
8
9
10
278
Production process/manufacturer
Is the manufacturer of the API and the medicinal product experienced in the production of biopharmaceuticals?
How long has the biopharmaceutical been on the market?
How extensive is the clinical experience with each individual biosimilar? Expressed as the number of patient days worldwide
Product specifications
Are there any differences in drug formulation and administration in comparison to the reference product or other biosimilars?
What is the number of registered indications for the biopharmaceutical/biosimilar?
Clinical efficacy
Are there different results in comparison to the reference product?
Clinical safety and tolerability
Which (serious and mild) adverse events and in which frequency were they reported in clinical trials with the biopharmaceutical?
Are there any contraindications, precautions or warnings which are different compared with the reference product?
Is immunogenicity, as far as known, caused by a homogeneous type of antibody or is there a high intra-individual or inter-individual variability? Is there a difference
between biosimilar products regarding drug antibody homogenicity?
Are there differences in the incidence and severity of drug interactions?
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
A2: Is the exact production site of API and final product always
known to EMA?
Since 2 January 2013 a new European requirement exists for
importing APIs. All APIs must have been manufactured at a
GMP site (GMP must be equivalent to EU’s GMP as a
minimum). From 2 July 2013 onwards, according to article
46b2b of the EU Directive 2011/62/EU, the importer needs to
request a document by the local competent authority in which it
is written that the manufacturer complies with GMP standards
to at least the same standard as EU GMP.26 The ICH Q7 document provides guidelines for manufacturing quality management
of APIs and harmonises GMP standards in the EU, the USA and
Japan.29
All sites involved in the production of the finished medicinal
product and of the active substances must be described (name and
detailed address, including building reference) in Module 1.2 of
the application for a marketing authorisation together with a
description of the steps performed. This should include, among
other things, active substance and finished product manufacture.30
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A3: Have all production facilities of API and final product been
checked by EMA or other authorities?
The production site is subject to inspection by EMA inspectors
or other authorities. A finished product can be formulated with
APIs or excipients produced under Chinese and or Indian GMP
(which is estimated to be 80% of bulk APIs). It is EMA’s role to
review this process as a part of the registration procedure.
In relation to the document for third country manufacturers
published by EMA, information about any previous EEA
(European Economic Area) inspection in the last 2–3 years and/
or any planned EEA inspections should be provided and should
include details of the inspection dates, product category
inspected and the name of the inspecting competent authority.30
Documents that should be attached to Module 1 of the application include the following.
For all sites (other than active substance manufacturers)
located in third countries where a Mutual Recognition
Agreement (MRA) or other relevant agreement is in place, a
MRA certificate (not older than 3 years) from the local competent authority that carried out the inspection and/ or a GMP
certificate from the EEA inspecting competent authority (if the
site has been inspected by an EEA competent authority in the
last 2–3 years) is required.
For all sites other than active substance manufacturers,
located in third countries with no MRA, a GMP certificate from
the EEA inspecting competent authority (if the site has been
inspected by an EEA competent authority in the last 2–3 years)
is necessary. Alternatively, a reference can be made to the appropriate entry in the EudraGMP database.
In addition to the above, a copy of the registration or other
document analogous to the manufacturing authorisation from
the local competent authority must demonstrate that the site is
authorised to manufacture a product or pharmaceutical form.
Also details of any inspection performed by authorities other
than the EEA authorities (eg, a GMP certificate or similar statement from the competent authority which carried out the
inspection) must be provided.30
According to EMA an operational MRA provides assurance
that equivalent GMP standards are applied by the parties of the
MRA and removes the need for additional inspection and
re-controls at import. This is applicable for production plants
located in the following countries: Australia, Canada,
Switzerland, Japan, New Zealand, the USA.30
Once validated, adding a new site or changing the steps of manufacture/batch release described under Module 1.2 (ie, application
form) of the application is normally not allowed during the
210-day review period. Any additional site or change in the manufacturing or batch release arrangements should be submitted as a
variation after the granting of the marketing authorisation.30
In the case of Omnitrope, during its development, several
changes were introduced, such as a transfer to a production
plant in the USA and a re-transfer to a production plant in
Austria. Several improvements to the purification process were
implemented at these manufacturing sites. Due to these major
changes, additional similarity information had to be submitted
and reviewed by EMA.31
During the process development of Ratiograstim, the site of
fermentation and purification was changed when the manufacturing was transferred to a GMP production facility. In a public
assessment report for Ratiograstim, EMA rapporteurs explained
that the master cell bank and working cell bank complied with
current GMP.32
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A4: Are all recalls reported to EMA?
MAHs, manufacturers and importers are obliged to report to
EMA whenever a centrally authorised product is not available
because of a shortage of supply or when a recall has to be done.
In addition, MAHs are requested to inform EMA of any prohibition or restriction imposed by the responsible competent
authority of any country in which the medicinal product is
placed on the market and of any other new information.33
The following FDA webpage has a section that shows current
biological product shortages, including the reasons for the shortage and if they have been resolved:http://www.fda.gov/
BiologicsBloodVaccines/SafetyAvailability/Shortages/default.htm.
On the current version of the EMA website it is not possible to run
a search on the criteria ‘show me all medicines with shortages’.
This requirement has been noted and this type of functionality is
expected to become available in the future. Currently, when a
search is performed for a medicine by product name on the
website, the medicine page returned will show any information
available on shortages on the right-hand side of the page.
EMA only communicates on shortages if they concern a centrally authorised medicine. This is the case if the shortage is
affecting more than one EU Member State and once the EMA
has issued a recommendation. EMA asks the National
Competent Authorities (NCAs) of individual member states for
a more complete picture on shortages of nationally authorised
products and centrally authorised products in a particular
member state. This criterion is adequately covered by EMA and
NCAs and is not included in the final set of selection criteria.
A5: Is the manufacturer experienced in the production of
biopharmaceuticals?
This criterion is included in the final set of criteria.
Experience of biopharmaceuticals production: score 10% per
year of experience. Therefore, the score is 40% if the company
has been in production for 4 years.
A6: Which national authorities are responsible for inspecting the
manufacturing site?
This information is covered in Module 1 of the EMA application where administrative information is requested. On the
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
279
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
following link information can be assessed about the national
authorities inside the EU:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/
general/general_content_000155.jsp&mid=WC0b01
ac0580036d63.
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A7: How long has the biopharmaceutical been on the market?
This criterion is included in the final set of criteria. The criterion is introduced as an estimate of the guaranteed safety of the
biosimilar.
This is a standard SOJA criterion: 10% for every year on the
market. This is used for a comparison of different chemical
entities of small molecules. Because biosimilars are similar to
the reference product, a flatter scale is used for biosimilars: 25%
per year. If a biosimilar is on the market for 3 years, this
product will score 75%.
A8: How extensive is the clinical experience with each individual
biosimilar? Expressed as the number of patient days worldwide
This criterion is included in the final set of criteria. The criterion is introduced as an estimate of the guaranteed safety of the
biosimilar.
This is a standard SOJA criterion: 1% for every million days
of experience. This is used for a comparison of different chemical entities. Because biosimilars are similar to the reference
product, a flatter scale is used for biosimilars: 10% per million
patient days of experience. If the clinical experience with a biosimilar is 4 million patient days, this product will score 40%.
A9: Does the manufacturer guarantee active information about
major changes of the manufacturing process?
Quality control and changes in the production process are
included to the list of criteria set up by Krämer et al.4 The
erythropoietin case has made clear that changes in the production process may affect the properties of the final product in a
negative way.
Erythropoietin α (EPO α; Eprex) was used extensively for the
treatment of anaemia associated with chronic renal failure. An
increase in the incidence of pure red cell aplasia associated with
EPO α occurred in 1998. After that, investigations were initiated
to identify the cause of the increase in the immunogenicity of
Eprex. Rubber stoppers were in use since the introduction of
Eprex pre-filled syringes for subcutaneous administration. The
replacement of human serum albumin with polysorbate 80 in
1998 appears to have resulted in a change in the leaching of
potentially immunogenic compounds from the uncoated rubber
stoppers.34 In addition, it was discussed that the new formulation was less stable and an increased aggregation rate caused
immunogenic reactions. This example shows that it is necessary
to inform EMA about any changes in the manufacturing process
because it might affect the efficacy and safety.
The ICH guidance (ICH-Q5E) concludes that products must
have highly similar quality characteristics before and after
changes of the manufacturing process and that safety and efficacy of the drug product is not affected.35 EMA published a
document that underlines the importance of performing a
proper comparability exercise in its guideline on comparability
of medicinal products containing biotechnology-derived products as active substance non-clinical and clinical issues.8
The goal of the comparability exercise is to ensure the quality,
safety and efficacy of a drug product after changing the manufacturing process. Therefore all relevant data must be registered and
280
evaluated that might have any impact on the drug product characteristics. Comparability can be assessed on a combination of analytical testing, biological assays, and in some cases, non-clinical
and clinical data. The manufacturer should confirm that the specifications after the process change are appropriate to ensure
product quality. Of course, this is also true for the reference
product. Schiestl et al36 investigated the variability in quality characteristics of different batches of Aranesp, Mabthera and Enbrel.
Major structural changes in protein composition that can alter the
pharmacokinetics and biological activity were found by chemical
analysis of these products. The observed changes occurred because
of changes in growth conditions or purification steps. All batches
of the products remained on the market during the investigation
period. The health authorities did not reason that the observed
changes would affect the safety and efficacy profiles of these originator products. Therefore it can be concluded that the considerations to maintain a product on the market after production
process changes are multifactorial and are not solely based on the
chemical characteristics of the questioned protein products. The
extent of the comparability exercise depends on what is known
about its possible impact on safety and efficacy of the product.
Sometimes additional comparative information is needed at the
preclinical and clinical level. The objective of the ICH Q5E document is to provide principles for assessing the comparability of biotechnological or biological products before and after changes that
are made in the manufacturing process for the drug substance or
drug product.35
For hospital pharmacists and clinicians it would be useful to
check whether there is a causal relation between an observed
adverse drug event and a product change. The EMA webpage
provides information about changes in the manufacturing
process of specific biological medicinal products .37
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A10: Is the reference medicinal product authorised in the
European Community?
At the moment this is a prerequisite according to the biosimilar
authorisation legislation. The reference medicinal product must
be a medicinal product authorised in the European Community.
However, changes are under discussion.
Because this is a valid prerequisite, this criterion was not
included in the final set of selection criteria.
A11: How has it been validated that the production of the API
and final product is always performed under the same conditions?
The EU has introduced new rules as an amendment of Directive
2011/62/EU for importing APIs to stop the import of substandard or counterfeit pharmaceutical ingredients.26 Competent
authorities of the exporting country must confirm to the broker
that the production site of an API complies with EU GMP rules
and that the production plant is subject to control.
Manufacturing standards for APIs are those of the ICH Q7.29
The manufacturing and purification processes have to be
properly described and the process validation studies and the
in-process control system must be considered acceptable to
EMA. Product European public assessment reports (EPARs)
explain that validation programmes were developed or implemented and have limits set. In these documents individual physicians and pharmacists cannot access further information, but
there is a general view of the validation.
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
A12: Has EMA checked quality control systems of the producers
of API and final product?
These data are described in the EPARs of the individual
products. See Filgrastim Hexal and Nivestim documents as
examples.38 39
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A13: Are data concerning batch reproducibility (inter-batch and
intra-batch variability) available at EMA before and after
approval?
These data are described in the EPAR scientific discussions of
the individual products. See Nivestim scientific discussion as an
example.39
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A14: Are specifications of quality control of the MAH/
manufacturer known to EMA and assessed by EMA?
Analytical aspects of validation are covered by the EMA document ‘Guideline on bioanalytical method validation’.40
The manufacturer has to present quality data to EMA for a
marketing authorisation application. The registration dossier
includes data to establish the quality of the product, including
definitions and descriptions of the manufacturing process,
and associated quality checks and standards;
data on consistency of manufacturing (quality control of the
process); data on analytical tests (molecular structure, potency
and purity profile); data on stability of the product. Most of
these data are to be presented as a comprehensive comparability
exercise with the reference product.41
It may be the case that these data are protected by EMA as
confidential information. Even a company developing a biosimilar monoclonal antibody usually has no data on critical
in-process controls and intermediates in the manufacturing
process of the innovator.
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A15: Is it taken into consideration whether materials of animal
origin or potentially allergenic materials are used during the
production or formulation?
If an application relates to a medicinal product which contains
or uses in the manufacture materials of animal origin or these
are used during the production process, applicants are requested
to complete tables and information established on ‘Note for
guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products’ and this
information will be included in Module 3.2.R of the common
technical document (CTD).42
For materials of animal origin other than those covered by
the ‘Note for guidance on minimising the risk of transmitting
animal spongiform encephalopathy agents via medicinal products’ applicants are requested to complete table B on ‘Other
materials of animal origin’. If an application relates to a medicinal product which contains materials of human origin or these
are used during the production process, applicants are requested
to complete table C on ‘Albumin and other human tissue
derived products’.30
When cell cultures are used for the production of the API,
the information is given in the EPAR. The type of cells (expression systems) that are used to produce these products are mentioned. For instance, in the case of EPO the originator used
mammalian Chinese hamster ovary cells as host cells and the
biosimilar product Dynepo was produced by human cell lines.
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A16: Does EMA take into consideration where clinical studies
were performed or is only the quality of the study an item of
discussion?
This has been published on the EMA web page. On 16 April
2012, the document published is based on ethical and GCP
aspects of clinical trials of medicinal products for human use
conducted outside of the EU/EEA and submitted in marketing
authorisation applications to the EU regulatory authorities.
This document strengthens existing processes to provide assurance to regulators and stakeholders that clinical trials meet the
required ethical and GCP standards, no matter where in the world
they have been conducted. The reflection paper is part of the
Agency’s strategy developed to address the challenges arising from
the increasing globalisation of clinical research: no matter where
you stand today, most clinical trials are being conducted somewhere else in the world, under a different regulatory framework
and in a different cultural setting. Yet regulators, healthcare professionals and patients worldwide all rely on the same trial data when
making decisions on whether to authorise a medicine to come to
the market or not and on whether to use a medicine or not.43
Nowadays, applicants and/or MAHs will be inspected (GCP
inspection) within routine inspections required to ensure that
information is available. Moreover, the conduct of clinical trials in
accordance with ethical requirements will be checked.
When a GCP inspection is performed, the reasons for inspection should be described. Relevant information from the inspection report may be made publicly accessible. The actions taken
should be reflected in the public assessment reports.43
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
A17: How is batch consistency ensured by the manufacturer and/
or by third party?
Small variations are an indicator of a consistent manufacturing
process. In some cases it might be that the manufacturer lacks
experience in batch conformity because of a limited number of
batches produced. Access to batch certificates of three recently
produced batches by the MAH allows EMA to check and document pharmaceutical quality and also strengthens mutual trust.
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
B: Product specifications
B1: Are there any differences in isoform pattern in comparison to
the reference product or other biosimilars?
The therapeutic relevance of a difference in isoform patterns
between a biosimilar and the originator product is addressed by
ICH and EMA guidelines. See EMA and ICH guidelines.8 35
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
B2: Are there any differences in drug formulation and
administration in comparison to the reference product or other
biosimilars?
The packaging material may affect the integrity of a biological
medicinal product. Protein instabilities caused by adsorption
from equipment surfaces or due to shed particles, such as plasticisers, can be caused by operational or procedural changes or by
changing the surface or equipment type itself (eg, membranes,
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
281
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
pumps and tubing). Similarly, compatibility studies can identify
problems with particular container closures and delivery
devices.44 In STEPSelect tenders such an assessment is undertaken based on the National Quality Control and Risk
Assessment of licensed medicinal products to assess and score
individual entities and this methodology would be applicable.19
This is included in the final set of criteria, as separate criteria.
The first four criteria are relevant from a patient’s perspective;
the last two are relevant from a pharmacy perspective.
The scoring is dependent on the product classes. General
scoring is not possible.
1. Dosage form or route of administration. A patient intuitive
device will score higher than a standard prefilled syringe or
injection vial.
2. Route of administration (higher score when more routes of
administration are possible, eg, subcutaneous, intramuscular,
intravenous).
3. More strengths available. The higher the number of
strengths available and the more patient friendly, the higher
the score.
4. Dosage frequency: higher score for less frequent administration.
5. Room temperature>fridge>frozen: decreasing scoring.
6. Extended stability: higher score.
B3: What is the number of registered indications for the
biopharmaceutical/biosimilar?
This criterion is included in the final set of criteria.
This is a standard SOJA criterion and is relevant from a pharmacy perspective. The higher the number of approved indications and the higher the applicability, the higher the scoring.
This depends on the drug class in question and no general
scoring is possible.
C: Reliability of supply
C1: Does the supplier reliably guarantee the supply of the
biosimilar over a long time period?
In this section, we have included the lead time that the supplier
guarantees and the actions taken after stock outs to evaluate
how the manufacturer and supplier manage these problems.
Availability of the drug product is important because otherwise
unwanted switches are necessary.
A continuous and reliable supply is a prerequisite. Do not
consider formulary inclusion if the local supplier cannot give
guarantees about timely delivery for the contract period.
This criterion is part of STEPSelect where shortages of stock
clauses and penalties for failure to supply are included in the
special terms and conditions of the contract for the purchase of
pharmaceuticals to which companies must comply and hence is
a prerequisite.19
This criterion should be a prerequisite for individual contracts
between hospitals and suppliers and is not included in the final
set of selection criteria.
D: Good handling practice
D1: Is the biosimilar delivered according to good storage (GSP)
and distribution practice (GDP)?
To maintain the original quality of pharmaceutical products,
every party active in the distribution chain has to comply with
the applicable legislation and regulations. Every activity in the
distribution of pharmaceutical products should be carried out
according to the principles of GSP and GDP as applicable.45 46
Manufacturers should apply principles of GDP in the distribution chain and in addition should select a shipping company
that achieves quality requirements. Therefore the probability of
282
supply chain related detriments, which could, for example,
affect the immunogenic profile or shelf life, is reduced. Public
health considerations demand that pharmaceutical products
should not be treated in the same way as ordinary commodities.
Their manufacture and subsequent handling within the distribution chain, nationally and internationally, must meet WHO
guidelines and should be rigorously controlled. These precautions serve to assure the quality of products, and to prevent the
infiltration of illicit products into the supply system.
For medicinal products imported from third countries, retesting of each batch within the EEA upon importation is required
unless an MRA or other relevant agreement covering GMP for
the product under consideration is operating within the country
where the medicinal product is manufactured. If such an MRA
is in operation, batch controls/tests carried out in the country
where the product is manufactured are acceptable. It should be
noted that MRAs cover batch control/testing and do not cover
batch release. Batch release must take place in the EEA territory
for every production batch released to market in the EEA, irrespective of whether an MRA with the exporting country is in
place or not. Laboratories used for contract testing upon
importation of medicinal products manufactured in third countries may be located in any EEA country.30
This criterion is adequately covered by EMA and is not
included in the final set of selection criteria.
E: Clinical efficacy
E1: Is the clinical development programme consistent with the
current regulatory requirement?
This is extensively discussed in the various EMA assessments.
Various additional guidelines were developed during the last few
years ( product specific and non-specific).
In most development programmes for biosimilar medicines
comparability is demonstrated in a stepwise process that starts
with pharmacokinetics and pharmacodynamics studies followed
by clinical efficacy and safety trials. In efficacy trials an equivalence
design is used in most cases. Endpoints for trials are clearly
defined in certain product-class-specific guidelines by Committee
for Medicinal Products for Human use experts. These primary
endpoints do not necessarily have to be the same as those used in
the trials with the originator product but deviations from these
guidelines have to be justified. The margins of clinical comparability should be pre-specified with respect to statistical and clinical
aspects by using the data of the reference product.8
In our opinion this criterion is adequately covered by EMA
and is not included in the final set of selection criteria.
E2: Which clinical trials in which patient populations with which
designs, endpoints and results were performed?
The criterion is introduced as an estimate of the documentation
of the biosimilar in randomised clinical trials.
For biosimilar products that are very similar to the reference
product abridged clinical development programmes can be performed because experience is gained with the originator
product. Nevertheless biosimilars have to go through the whole
registration process and in the end the average time to positive
opinion issued by the EMA is longer than for originator biological medicines.47
For products that are less similar to their reference products,
more extensive clinical studies are to be done and extrapolation
of indications will be more unlikely. An extended clinical study
programme would favour products that had not proven close
similarity to the reference product because that product would
have to demonstrate efficacy and safety in a study with a higher
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
number of included patients. Therefore, this criterion was not
included in the final set of criteria.
E3: Are there different results in comparison to the reference
product?
This criterion is included in the final set of criteria.
This is a standard SOJA criterion and is usually assigned the
highest weight of all selection criteria. No general scoring is
possible. The higher the efficacy in randomised clinical trials,
the higher the score. If there are no documented differences in
clinical efficacy, both drugs will have identical scores.
F: Clinical safety and tolerability
F1: Which (serious and mild) adverse events and in which
frequency were they reported in clinical trials with the
biopharmaceutical?
This criterion is included in the final set of criteria.
This is a standard SOJA criterion and is usually given a high
relative weight. No general scoring is possible. The numbers of
patients included in clinical trials will usually be insufficient to
identify rare side effects and to make statements concerning
safety. Only the judgement of tolerability is possible here. To
make statements on safety, many more patients would have to
be included and the duration of studies would have to be much
longer. The better the tolerability in clinical trials, the higher
the score for the drug in question.
Besides clinical trials, data from pharmacovigilance studies
will also be taken into consideration in the judgement of relative
safety (see section G).
F2: Are there any contraindications, precautions or warnings
which are different compared with the reference product?
This criterion is included in the final set of criteria.
This is a standard InforMatrix criterion.18 A large number of
contraindications or many warnings or precautions may limit
the usefulness of the drug for the treating physician. No general
score is possible; scoring depends on the specific contraindications and warnings for specific drugs. The more contraindications and precautions, the lower the score.
F3: Is immunogenicity, as far as known, caused by a
homogeneous type of antibody or is there a high intra-individual
or inter-individual variability? Is there a difference between
biosimilar products regarding drug antibody homogenicity?
This criterion is included in the final set of criteria.
Immunogenicity can affect the safety and efficacy of biosimilars
that may lead to clinical consequences such as adverse effects and
reduction of efficacy. Immunogenicity is influenced by factors
relating to the pharmacological active substance itself. Aggregation
of the protein product can also induce immunogenicity, including
manufacturing changes, impurities as by products (leachates or leachables=lixiviate which may migrate from the primary packaging
into the drug product). Plasticisers, antioxidants and allergens can
be leached from rubber in container closures causing product
impurities. The presence of degradation products, host cell products and formulation changes and the use of a different packaging system (containers and closures) are other factors that
influence safety and tolerability.48–50 In addition to these aspects,
immunogenicity may be influenced by factors related to the individual susceptibility of the patient (eg, patients who are immunocompromised), disease, treatment, dose, route or schedule of
administration. It is worth mentioning that testing strategies or
analytical methods should guarantee a correct immunogenicity
assessment. The assessment of immunogenicity is covered in an
EMA guideline.51 These immunogenicity assays should guarantee
the safety and efficacy of biopharmaceuticals.
The immunogenicity of biopharmaceuticals/biosimilars often
cannot be fully predicted using preclinical (non-clinical) in vitro
and ex vivo studies and clinical immunogenicity studies are
usually required before approval and sometimes also after
approval. Moreover, patient-specific immunogenicity may sometimes only emerge after extensive exposure and usage. Further
systematic immunogenicity testing may also be required after
gaining marketing authorisation. Assessment of immunogenicity
may be part of post-approval risk management plans (RMPs)
and pharmacovigilance activities.51
No general score is possible. The score will depend on the
available data for each individual biological medicinal product.
The more (severe) reactions, the lower the score for the specific
biosimilar.
F4: Are there differences in the incidence and severity of drug
interactions?
This criterion is included in the final set of criteria.
This is a standard SOJA criterion. No general scoring is possible. The lower the incidence and severity of drug interactions,
the higher the score for the drug in question. However, it seems
unlikely that there will be relevant differences between the reference drug and biosimilars regarding this criterion.
F5: Are there differences in the incidence of local reactions?
This criterion is not included in the final set of criteria but is
taken into consideration under criterion F1.
G: Pharmacovigilance
In this section we have included questions about the risks associated with an unwanted immune response established and if
there are any specific risk management strategies when the
manufacturing process changes.
G1: Does the MAH have a 24 h phone number equipped with
adequate personnel to report adverse events?
This criterion should be a prerequisite for individual contracts
between hospitals and suppliers and is not included in the final
set of selection criteria.
G2: How is pharmacovigilance controlled?
Pharmacovigilance is a continuous process as is the case for biosimilar medicinal products. Knowledge about the equilibrium
between efficacy and safety from the pre-authorisation period
can change over time after market access. The expanding
number of patients exposed to the drug and their characteristics
and subtle changes to a complex medicinal product can have an
impact on this equilibrium. EMA considers the detection, assessment, minimisation and communication about the associated
risks to be the responsibility of the MAH. The MAH must
provide a RMP in the application as a part of the CTD. In addition, the MAH must have a qualified person who is continuously available to deal with pharmacovigilance issues. After
approval, the MAH should promptly report to the competent
authorities or directly to EMA for centrally authorised products
in the case of pharmacovigilance issues.9
EU legislation about pharmacovigilance and reporting of nonserious unexpected adverse events is given in EC regulations
EC726/2004 and EC 540/95, respectively.52 53 These regulations are supported by guidelines condensed in the Eudralex
volume 9 ‘Pharmacovigilance’.54 This criterion is adequately
covered by EMA.
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
283
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
Healthcare providers can access information about the focus
areas of the RMP for the individual product during postmarketing surveillance by searching the website of the EMA
where EPAR scientific discussion can be found.37
For healthcare providers, as part of the pharmacovigilance
system, it is important to know that product identification is crucial
when reporting an adverse event. Only the brand name and the
batch number can identify the product in the case of biosimilar
medicinal products.9 The use of international non-proprietary
names (generic names) and misconceptions about interchangeability
between biosimilar and originator medicinal products can stress problems of traceability of the incriminated product.
CONCLUSION
The checklist created by Krämer et al makes it possible to make
informed decisions about the selection and evaluation of biopharmaceuticals and biosimilars. In this article we have added
or introduced some issues and questions to complement
Krämer’s checklist. An expert panel reviewed all issues and to
what extent they are covered in EMA laws and regulations. This
resulted in a compact and practical set of questions useful for
clinicians and pharmacists who want to make an informed decision when selecting biopharmaceuticals.
Since the first biosimilar guidelines were implemented some
products have been authorised and additional applications are
under review. The number of advice notes and revisions made
by EMA on the assessment and development of biosimilars has
increased enormously. As a consequence, some issues about the
selection criteria might change or indeed other questions might
be added. EMA proposed to re-evaluate some topics about biosimilars as a result of the experience gained during the last few
years. In December 2012 an overarching guideline by EMA
established the general principles to prove comparability
between a biosimilar and a reference product.55
The education of healthcare professionals about the differences
between biosimilars and originator products is another issue to
take into account. We hope that this article contributes to the
general knowledge about biosimilar and biopharmaceutical products to help healthcare professionals make well informed choices.
We have not taken the criterion acquisition cost into consideration. The present set of criteria is intended to allow a quick comparison of the reference product and available biosimilars. Usually,
the reference product will show the highest score, based on its
more extensive clinical documentation. It is up to the individual
hospital to determine which difference in overall score is acceptable
(for instance 10%). All products that show a score that is less than
10% lower than the drug with the highest score proceed to the
second phase of the drug formulary evaluation. In that phase the
(tendered or procured) acquisition cost will be the only criterion.
However, it is important to emphasise that the number of biosimilars may increase rapidly due to the expiration of patents, therefore constant review and assessment of the checklist and the
regulatory requirements and revisions for biosimilars will be necessary. It is our intention to work together as European hospital
pharmacists to form a team of pharmacists with expert knowledge
on specific drug classes and their relevant biosimilars.i This expert
team will judge the drugs using the criteria suggested in this paper
and their assessments will be made available on the internet in an
interactive manner. Hospital pharmacists from all over Europe can
then enter their own relative weight to the selection criteria,
thereby making a personal but evidence-based selection of biosimilars to be used in their own hospitals.
What this paper adds
What is already known on this subject
▸ In the past few years regulatory bodies like the European
Medicines Agency (EMA) and the US Food and Drug
Administration (FDA) have built up extensive knowledge on
evaluating comparability between a biosimilar and its
originator market variant. This knowledge is reflected in a
capacious set of guidelines and regulations.
▸ When starting biosimilar therapy in patients it is difficult for
individual clinicians and pharmacists to judge efficacy and
safety because of the complex nature of biosimilars and
their reference products.
What this study adds
▸ A panel of biosimilar experts reviewed guidelines and
regulations of EMA and FDA and judged what would be
relevant for biosimilar selection criteria in clinical practice.
▸ This article provides a set of 10 clinically relevant selection
criteria to which individual weights can be assigned to
subsequently score the originator and the biosimilar product.
Acknowledgements The authors would like to thank Dr Joerg Windisch, Sandoz
for his comments that helped to improve this manuscript.
Contributors All authors delivered a proportionate contribution to the creation of
this manuscript.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
REFERENCES
1
2
3
4
5
6
7
8
9
10
i
The authors of this article are creating a European panel of experts
to evaluate biosimilars. Hospital pharmacists with expert knowledge
of the following topics are invited to apply to join the panel:
biosimilars in general; erythropoietins; filgrastim and other growth
factors; somatropin. Please contact [email protected] or r.
[email protected] for further information.
284
11
12
European Commission. What you need to know about biosimilar medicinal
products. European Commission. 2013. http://ec.europa.eu/enterprise/sectors/
healthcare/files/docs/biosimilars_report_en.pdf (accessed 3 Jul 2013).
Declerck PJ, Simoens S. A European perspective on the market accessibility of
biosimilars. Biosimilars 2012;2:33–40.
Misra A. Are biosimilars really generics? Expert Opin Biol Ther 2010;10:489–94.
Krämer I, Tredree R, Vulto A. Points to consider in the evaluation of
biopharmaceuticals. Eur J Hosp Pharm Prac 2008;14:73–6.
Chirino AJ, Mire-Sluis A. Characterizing biological products and assessing
comparability following manufacturing changes. Nat Biotech 2006;22:1383–91.
Schellekens H. Biosimilar epoetins: how similar are they? Eur J Hosp Pharm
2004;3:43–7.
Büttel IC, Chamberlain P. Taking immunogenicity assessment of therapeutic proteins
to the next level. Biologicals 2011;39:100–9.
European Medicines Agency. Guideline on comparability of medicinal products
containing biotechnology derived products as active substance non-clinical and
clinical issues. European Medicines Agency. April 2013. http://www.ema.europa.eu/
docs/en_GB/document_library/Scientific_guideline/2013/06/WC500144124.pdf
(accessed 3 Jul 2013).
Zuniga L, Calvo B. Biosimilars: pharmacovigilance and risk management.
Pharmacoepidemiol Drug Saf 2010;19:661–9.
Pro Pharma Communications International, GaBI Online—Generics and Biosimilars
Initiative. Biosimilars-not-so-far-so-fast. GaBI Online. 18 March 2013. http://www.
genengnews.com/insight-and-intelligence/biosimilars-not-so-far-so-fast/77899781/
(accessed 9 Apr 2013).
Rovira J, Lindner L, Gimenez E, et al. Biosimilars in the European market. GaBI J
2013;2:30–5.
Food and Drug Administration. Guidance for industry on biosimilars. Q & As
regarding implementation of the BPCI Act of 2009: Questions and Answers Part I,
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Q.I.14. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm259809.htm (accessed 15 Aug 2013).
Pro Pharma Communications International, GaBI Online—Generics and Biosimilars
Initiative. Interchangeability not covered in FDA draft biosimilar guidance. GaBI
Online. 17 February 2012. http://www.gabionline.net/Guidelines/
Interchangeability-not-covered-in-FDA-draft-biosimilar-guidance (accessed 18 Apr
2013).
European Medicines Agency. Questions and answers on biosimilar medicines
(similar biologic medicinal products). European Medicines Agency. 27 September
2012. http://www.emea.europa.eu/docs/en_GB/document_library/Medicine_QA/
2009/12/WC500020062.pdf. (accessed 27 Apr 2013).
Zuñiga L, Calvo B. Regulatory aspects of biosimilars in Europe. Trends Biotechnol
2009;27:385–7.
Pharma and Healthcare Insight. Dutch health insurers to reimburse biosimilars. 25
September 2009. http://www.pharmaceuticalsinsight.com/file/81624/
dutch-health-insurers-to-reimburse-biosimilars.html (accessed 18 Apr 2013).
Janknegt R, Steenhoek A. The System of Objectified Judgement Analysis. A tool in
rational drug selection for formulary purposes. Drugs 1997;53:550–62.
Brenninkmeijer R, Mairs J, Timoney M, et al. InforMatrix as an alternative tool in
rational and transparent drug-decision making. Expert Opin Pharmacother 2007;8
(Suppl 1):S31–6.
Scott M, Timoney M, Mairs J, et al. Safe Therapeutic Economic Pharmaceutical
Selection (STEPS): development, introduction and use in Northern Ireland. Expert
Opin Pharmacother 2007;8(Suppl 1):S57–63.
European Medicines Agency. Pharmaceutical Quality System (ICHQ10). European
Medicines Agency. 21 January 2011. http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2009/09/WC500002871.pdf (accessed 17 Apr
2013).
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). Guidance for industry Q8 (R2)
Pharmaceutical development. Food and Drug Administration. 10 November 2009.
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073507.pdf (accessed 17
Apr 2013).
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). Guidance for industry Q9
Quality risk management. Food and Drug Administration. June 2006. http://www.
fda.gov/downloads/Drugs/.../Guidances/ucm073511.pdf (accessed 17 Apr 2013).
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). Guidance for industry Q10
Pharmaceutical quality system. Food and Drug Administration. April 2009. http://
www.fda.gov/downloads/Drugs/Guidances/ucm073517.pdf (accessed 17 Apr 2013).
International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). Guidance for industry Q11 Development
and manufacture of drug substances. Food and Drug Administration. November
2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/UCM261078.pdf (accessed 17 Apr 2013).
European Medicines Agency. CPMP/ICH/365/96, ICH Topic Q6B Specifications: Test
procedures and acceptance criteria for biotechnological/biological products.
September 2009. http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2009/09/WC500002824.pdf (accessed 17 Apr 2013).
European Parliament. Directive 2011/62/EU of the European Parliament and of the
Council of 8 June 2011. European Commission. 8 June 2011. http://ec.europa.eu/health/
files/eudralex/vol-1/dir_2011_62/dir_2011_62_en.pdf (accessed 17 Apr 2013).
European Parliament. Commission Directive 91/356/EEC of 13 June 1991 laying
down the principles and guidelines of good manufacturing practice for medicinal
products for human use. EUR-Lex. 13 June 1991. http://eurlex.europa.eu/LexUriServ/
LexUriServ.do?uri=CELEX:31991L0356:en:NOT (accessed 25 Apr 2013).
European Parliament. Directive 2001/20/EC of the European Parliament and of the
Council of 4 April 2001 on the approximation of the laws, regulations and
administrative provisions of the Member States relating to the implementation
of good clinical practice in the conduct of clinical trials on medicinal products for
human use. EUR-Lex. 4 April 2001. http://eurlex.europa.eu/LexUriServ/LexUriServ.
do?uri=CELEX:32001L0020:en:NOT (accessed 25 Apr 2013).
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). Good manufacturing practice
guide for active pharmaceutical ingredients Q7. 10 November 2000. http://www.ich.
org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q7/Step4/Q7_
Guideline.pdf (accessed 17 Apr 2013).
European Medicines Agency. EMA/940451/2011, EMA Procedural advice for users
of the centralised procedure for similar biological medicinal products applications.
March 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_
and_procedural_guideline/2012/04/WC500125166.pdf (accessed 17 Apr 2013).
European Medicines Agency. Omnitrope EPAR—scientific discussion. 23 April 2008.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_
Discussion/human/000607/WC500043692.pdf (accessed 25 Apr 2013).
European Medicines Agency. Ratiograstim EPAR—scientific discussion. 29 September
2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_
assessment_report/human/000825/WC500047793.pdf (accessed 25 Apr 2013).
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
European Medicines Agency. EMEA/INS/GMP/23020/2007, An analysis of quality
product defects in the centralised procedure. European Medicines Agency. 18
January 2007. http://www.emea.europa.eu/docs/en_GB/document_library/
Regulatory_and_procedural_guideline/2009/10/WC500004420.pdf (accessed 17
Apr 2013).
Boven K, Knight J, Bader F, et al. Epoetin-associated pure red cell aplasia in
patients with chronic kidney disease: solving the mystery. Nephrol Dial Transplant
2005;20(Suppl 3):33–40.
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). Comparability of
biotechnological/biological products subject to changes in their
manufacturing process. 18 November 2004. http://www.ich.org/fileadmin/Public_
Web_Site/ICH_Products/Guidelines/Quality/Q5E/Step4/Q5E_Guideline.pdf (accessed
20 Apr 2013).
Schiestl M, Stangler T. Acceptable changes in quality attributes of glycosylated
biopharmaceuticals. Nat Biotechnol 2011;29:310–12.
European Medicines Agency. Procedural steps taken and scientific information after
authorization/Steps taken after authorisation when a cutoff date has been used.
http://www.ema.europa.eu > ‘Find Medicine’ > [name] > ‘Assessment history’ >
[name]: EPAR — Procedural steps taken and scientific information after
authorisation; for products licensed before the deadline also refer to ‘[name]: EPAR
—Steps taken after authorisation when a cutoff date has been used’ (accessed 20
Apr 2013).
European Medicines Agency. Filgrastim-Hexal EPAR—Public assessment report. 6
February 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_
Public_assessment_report/human/000918/WC500022471.pdf (accessed 27 Apr
2013).
European Medicines Agency. Nivestim EPAR—public assessment report. 8 June
2010. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_
assessment_report/human/001142/WC500093664.pdf (accessed 27 Apr 2013).
European Medicines Agency. EMEA/CHMP/EWP/192217/2009, Guideline on
bioanalytical method validation. 21 July 2011. http://www.ema.europa.eu/docs/en_
GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf (accessed 17
Apr 2013).
European Generic Medicines Association. Biosimilars handbook, second edition.
Brussels: Sage, 2011:29.
European Medicines Agency. EMA/410/01, Note for Guidance on minimising the
risk of transmitting animal spongiform encephalopathy agents via medicinal
products. 5 March 2011. http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2009/09/WC500003700.pdf (accessed 27 Apr 2013).
European Medicines Agency. EMA/121340/2011 Reflection paper on ethical and
GCP aspects of clinical trials of medicinal products for human use conducted
outside of the EU/EEA and submitted in marketing authorisation applications to the
EU Regulatory Authorities. 16 April 2012. http://www.ema.europa.eu/docs/en_GB/
document_library/Regulatory_and_procedural_guideline/2012/04/WC500125437.
pdf (accessed 17 Apr 2013).
Bee JS, Randolph TW, Carpenter JF, et al. Effects of surfaces and leachables on the
stability of biopharmaceuticals. J Pharm Sci 2011 Published Online First: 26 April
2011 doi:10.1002/jps.22597.
World Health Organization. Annex 5 Guidelines on good distribution practices for
pharmaceutical products. World Health Organization. 2010. http://www.who.int/
medicines/areas/quality_safety/quality_assurance/GoodDistributionPractices
TRS957Annex5.pdf (accessed 3 Jul 2013).
European Parliament. 2013/C68/01 Guidelines of 7 March 2013 on good
distribution practice of medicinal products for human use. EUR-Lex. 8 March 2013.
http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2013:068:0001:0014:EN:
PDF (accessed 3 Jul 2013).
Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum Dis
2013;72:315–18.
Sharma B. Immunogenicity of therapeutic proteins. Part 1: Impact of product
handling. Biotech Adv 2007;25:310–17.
Sharma B. Immunogenicity of therapeutic proteins. Part: 2: Impact of container
closure. Biotech Adv 2007;25:318–24.
Barbosa M. Immunogenicity of biotherapeutics in the context of developing
biosimilars and biobetters. Drug Discov Today 2011;16:345–53.
European Medicines Agency. EMEA/CHMP/BMWP/14327/2006, Guidelines on
immunogenicity assessment of biotechnology-derived therapeutic proteins. 13
December 2007. http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2009/09/WC500003946.pdf (accessed 17 Apr 2013).
European Parliament. Regulation EC 726/2004 of the European Parliament and of
the Council of 31 March 2004, laying down Community procedures for the
authorisation and supervision of medicinal products for human and veterinary use
and establishing a European Medicines Agency. European Medicines Agency. 30
April 2004. http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:
L:2004:136:0001:0033:en:PDF (accessed 27 Apr 2013).
European Parliament. Commission Regulation (EC) No 540/95 1995 March 10
laying down the arrangements for reporting suspected unexpected adverse reactions
which are not serious, whether arising in the Community or in a third country, to
285
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
Research
54
medicinal products for human or veterinary use authorized in accordance with the
provisions of Council Regulation (EEC) No 2309/93. European Commission. 1995.
http://ec.europa.eu/health/files/eudralex/vol-1/reg_1995_540/reg_1995_540_en.pdf
(accessed 27 Apr 2013).
European Parliament. Volume 9A of the Rules Governing Medicinal Products in the
European Union. Guidelines on pharmacovigilance for medicinal products for human
55
use. European Commission. September 2008. http://ec.europa.eu/health/files/
eudralex/vol-9/pdf/vol9a_09-2008_en.pdf (accessed 27 Apr 2013).
European Medicines Agency. EMA/CHMP/BMWP/403543/2010. Guideline on similar
biological medicinal products containing monoclonal antibodies—non-clinical and
clinical issues. 30 May 2012. http://www.ema.europa.eu/docs/en_GB/document_
library/Scientific_guideline/2012/06/WC500128686.pdf (accessed 17 Apr 2013).
REQUEST FOR EXPERTISE
The authors of this article are creating a European panel of experts to evaluate biosimilars. Hospital pharmacists with expert knowledge of the following topics are invited to apply to join the panel:
– Biosimilars in general
– Erythropoietins
– Filgrastim and other growth factors
– Somatropin
Please contact [email protected] or [email protected] for further information.
286
Boone N, et al. Eur J Hosp Pharm 2013;20:275–286. doi:10.1136/ejhpharm-2013-000370
Downloaded from ejhp.bmj.com on September 21, 2013 - Published by group.bmj.com
How to select a biosimilar
Niels Boone, Hugo van der Kuy, Mike Scott, et al.
Eur J Hosp Pharm 2013 20: 275-286 originally published online August
28, 2013
doi: 10.1136/ejhpharm-2013-000370
Updated information and services can be found at:
http://ejhp.bmj.com/content/20/5/275.full.html
These include:
References
This article cites 18 articles, 1 of which can be accessed free at:
http://ejhp.bmj.com/content/20/5/275.full.html#ref-list-1
Email alerting
service
Receive free email alerts when new articles cite this article. Sign up in
the box at the top right corner of the online article.
Notes
To request permissions go to:
http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to:
http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to:
http://group.bmj.com/subscribe/