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European regulatory guidelines for biosimilars

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					Nephrol Dial Transplant (2006) 21 [Suppl 5]: v17–v20
doi:10.1093/ndt/gfl477




European regulatory guidelines for biosimilars

Andrzej Wiecek1 and Ashraf Mikhail2

1
    Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, Poland and
2
    Department of Renal Medicine, Morriston Hospital, Swansea, UK


Abstract                                                                    proteins are highly dependent on each step of the
The impending arrival en masse of biosimilars on                            manufacturing process. The result is that different
Western markets is placing drug regulatory agencies                         manufacturing processes yield a unique product,
under pressure to realign their policies. Biosimilars                       which may have a distinctive safety and efficacy profile
require more rigorous assessments than traditional                          (hence the name ‘biosimilar’ instead of ‘biogeneric’,
chemical generics. This is because of the molecular                         which implies identity). A biosimilar may differ
complexity of recombinant proteins, and the complex-                        significantly from a reference brand product.
ity of biological manufacturing processes. Small                            Furthermore, such differences may not be detectable
differences can arise in a recombinant protein product                      with even state-of-the-art analytical techniques.
which are hard or impossible to detect with even state-                     The only certain way to assess the safety and
of-the-art analytical techniques. Yet, these differences                    efficacy of a biosimilar is to conduct pre-clinical and
can have significant impact on the safety and efficacy                      clinical tests.
of the drug. The European Medicines Agency (EMEA)
has taken the lead in issuing guidelines, most of which
are still under review. The guidelines advocate pre-                        Are current regulations adequate?
clinical and clinical testing of biosimilars prior
to market authorization, complemented by tailored                           Current European Union (EU) legislation is embodied
pharmacovigilance plans. These guidelines provide                           in three documents, dating from 2001 onwards. The
a valuable base from which to develop in this evolving                      first covers items such as blood-derived products
regulatory environment.                                                     and vaccines [1], without referring specifically to
                                                                            biotechnology-derived drugs. Article 10 contains a
Keywords: biopharmaceuticals; biosimilars; EMEA;                            paragraph which remains the object of contention:
regulatory guidelines                                                       ‘The applicant shall not be required to provide the
                                                                            results of toxicological and pharmacological tests or
                                                                            the results of clinical trials if he can demonstrate:
Introduction                                                                (i) either that the medicinal product is essentially similar
                                                                            to a medicinal product authorised in the Member
A generation of biotechnology-derived therapeutic                           State . . . (ii) or that the constituent or constituents of the
agents are reaching the end of their patent lives,                          medicinal product have a well established medicinal use,
heralding the market entry of biosimilars. However,                         with recognised efficacy and an acceptable level of
recombinant proteins are associated with a number                           safety, by means of a detailed scientific bibliography’.
of issues which distinguish them from traditional                           The first point importantly lacks a precise definition of
chemical drugs and their generics. Recombinant                              ‘essentially similar’, while the second ignores the
proteins are highly complex at the molecular level,                         significant differences that can occur between manufac-
and biological manufacturing processes are highly                           turing processes. An amendment in 2003 [2] describes
elaborate: they involve cloning, selection of a suitable                    recombinant proteins as a ‘new class of biological
cell line, fermentation, purification and formulation.                      medicinal product’, but provides no further guidance.
In addition, the therapeutic properties of recombinant                      The last update, in 2004 [3], begins to broach the topic
                                                                            of biosimilars, stating ‘Biological medicinal products
                                                                            similar to a reference medicinal product do not usually
                                                                            meet all the conditions to be considered as a generic
Correspondence and offprint requests to: A. Wiecek, Department
of Nephrology, Endocrinology and Metabolic Disease, Medical
                                                                            medicinal product mainly due to manufacturing process
University of Silesia, Francuscka St 20-40, 40-027 Katowice,                characteristics. When a biological medicinal product
Poland. Email: awiecek@spskm.katowice.pl                                    does not meet all the conditions to be considered as a
ß The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournals.org
v18                                                                                                   A. Wiecek and A. Mikhail
generic medicinal product, the results of appropriate
tests should be provided in order to fulfil the require-
ments related to safety (pre-clinical tests) or to efficacy
(clinical tests) or to both’. Although this amendment
recognizes the difference between biosimilars and
classical generics, the document does not delve any
deeper into the matter.
   The European Medicines Agency (EMEA), a decen-
tralized body of the EU, has taken the lead in bridging
the gap. The EMEA’s Committee for Proprietary
Medicinal Products (CPMP), and its descendant, the
Committee for Medicinal Products for Human Use
(CHMP), have issued a number of guidance documents.
The overarching document, CHMP/437 [4], sets the
scene by recognizing that the generic approach no
longer suffices where biosimilars are concerned. The          Fig. 1. Diagram illustrating the interactions within the European
                                                              Medicines Agency (EMEA) and between the EMEA and external
other documents can be categorized according to their         groups. Ongoing peer review and scientific advice is given between
focus on quality or clinical issues, or their focus on        the EMEA’s Committee for Medicinal Products for Human Use
changes to an existing manufacturing process or an            (CHMP) and various Working Parties (WPs). Discussion and input
entirely new process. An important distinction to be          is encouraged from practicing physicians (including nephrologists),
made in this regard is between ‘comparability’, which         National Control Authorities (NCAs), Clinical Trials Authorities
                                                              (CTAs), Working Parties (WPs), Scientific Advisory Groups (SGAs)
assesses products preceding and following a change in         and academics.
manufacturing process, and ‘similarity’, which assesses
products from entirely different manufacturing pro-
cesses, with a focus on safety and efficacy. The
guidelines pertaining to changes in a manufacturing
process have already been approved [4–6], although            EMEA guidelines
the document on quality issues will be superseded by
the QE5 document from the ICH (International
                                                              Guidelines for changes in a manufacturing process
Conference on Harmonisation). The ICH seeks to
harmonize regulatory processes across the US, Europe          The guidelines for quality [6] and clinical [7] studies
and Japan. EMEA guidelines relevant to new manu-              required after a change in a manufacturing process
facturing processes for biosimilars are still under review    advocate a case-by-case approach. The quality checks
[7,8]. They are supplemented by a number of Concept           depend on the nature of the recombinant protein and
Papers, which provide the basis for a case-by-case            the nature of the manufacturing change. Whether
approach.                                                     pre-clinical or clinical studies are required depends
                                                              chiefly on the results from the quality assessment, and
                                                              particularly on the ability of analytical techniques to
                                                              characterize the biological product. All variations must
EMEA structure                                                be tracked within the pharamacovigilance database for
                                                              the product.
European guidelines are being generated through
consultation both within the EMEA and externally
(Figure 1). Internally, the CHMP collaborates with
a number of Working Parties (WP) through scientific           Guidelines for novel manufacturing
                                                              processes (Biosimilars)
advice and peer review. An important WP is the
Biological WP (BWP) which operates closely with               The relevant guidelines, yet to be approved, were
the Safety WP and Quality WP. The BWP’s remit                 published in 2005 [7,8]. They reaffirm the principles
includes developing guidelines on quality and                 which are applicable to innovator companies, e.g.
clinical requirements for biologics, and participation        the applicants should demonstrate the consistency
in the shaping of ICH guidelines. Externally, the             and robustness of their manufacturing process.
EMEA/CHMP operates within a network including                 Studies for biosimilars always have to be carried out
Scientific Advisory Groups (SAGs), the National               in comparison with the original reference product.
Competent Authorities (NCAs) of EU Member                     They involve batteries of in vitro assays, impurity
States, patient groups, universities and academic             profiling, and clinical pharmacokinetic (PK) and
societies. Finally, the EMEA welcomes and encourages          pharmacodynamic (PD) studies. Generally, clinical
input from practicing physicians. Together, these             efficacy trials will be warranted, complemented by
groups aim to reach a consensus on medicinal                  immunogenicity tests using validated assays. As ever,
products containing biotechnology-derived active              a post-approval continued benefit-risk assessment
substances.                                                   (pharmacovigilance plan) is necessary.
European regulatory guidelines for biosimilars                                                                              v19
Biosimilar-specific guidelines                              ahead in providing guidance for national regulatory
                                                            bodies in Europe. The EMEA guidelines are, however,
The Concept Papers and their annexes provide
                                                            a work in progress, and readers should consult
guidance specific for certain biological products, and
                                                            the EMEA web site (www.emea.eu.int) for the latest
have been published for recombinant human insulin
                                                            updates.
[9,10], growth hormone (GH) [11,12], granulocyte
                                                               Some sections of the guidelines are still controver-
colony-stimulating factor (GCSF) [13,14] and epoetin
                                                            sial. For instance, it is stated that comparative clinical
(EPO) [15,16]. They provide specific details on the
                                                            trials can be foregone if the biosimilar can be
various studies which need to be carried out
                                                            characterized in detail by physicochemical and
for biosimilars, both pre-clinical and clinical. Further,
                                                            in vitro techniques, or alternatively that comparative
such Concept Papers will progressively appear accord-
                                                            PK/PD studies can replace clinical trials. The annex
ing to demand.
                                                            to the insulin Concept Paper echoes this: efficacy data
   The annexe to the insulin Concept Paper [9] places
                                                            need not be provided if equivalence can be concluded
special emphasis on the comparative nature (relative to
                                                            from PK and PD data. In contrast, the other three
an innovator brand) of the studies. The PK properties
                                                            Concept Papers regard comparative clinical studies
of the biosimilar and the reference product should
                                                            as a necessity. However, non-clinical studies cannot
be assessed in a single-dose crossover study using
                                                            guarantee similarity, and therefore should not be
subcutaneous administration. Provided that equiva-
                                                            allowed to replace clinical studies where biosimilars
lence can be concluded from PK and PD data, there
                                                            are concerned.
is no anticipated need for clinical efficacy studies.
                                                               The emphasis on adequate screening for immuno-
However, immunogenicity issues can only be settled by
                                                            genicity events is well-warranted, given the incidence
a clinical study with a comparative phase of at least
                                                            of PRCA. Post-marketing monitoring is an essential
6 months, followed by pharmacovigilance procedures.
                                                            component in tracking rare but serious adverse
   The annexe to the growth hormone Concept Paper
                                                            events like these. The guidelines state that immuno-
[11] resembles the insulin annex, with a few noteworthy
                                                            genicity analyses should be performed especially in
differences. Besides references to specific bioassays and
                                                            cases where repeated administration is proposed.
PD markers, the main difference is that equivalent
                                                            A useful addition to the guidelines would be to require
therapeutic efficacy between the biosimilar and
                                                            branding of biosimilars, to allow optimal and accurate
the reference product should be demonstrated in at
                                                            pharmacovigilance.
least one adequately powered, randomized, parallel
                                                               Currently, no legal framework exists in the US
group, confirmatory clinical trial. Treatment-naı¨ ve
                                                            for the approval of biosimilars, and the FDA have
children with growth hormone deficiency are
                                                            released no guidance documents. The EMEA has
recommended as the target population, as they
                                                            provided a valuable base for EU legislation to evolve
provide the most sensitive model.
                                                            from. However, if we wish to ensure patient safety
   The annexe to the EPO Concept Paper [15] outlines
                                                            with the arrival en masse of biosimilars to the market,
somewhat more stringent requirements, reflecting
                                                            it is imperative that their unique characteristics
the greater molecular complexity of EPO compared
                                                            be recognized. Accrued experience will then allow
with insulin or GH. At least two adequately powered,
                                                            regulatory authorities to optimally match guidelines
randomized, parallel group clinical trials are necessary.
                                                            to the genuine risks and benefits associated with
Safety data over at least 12 months from at
                                                            biosimilars.
least 300 patients treated with the biosimilar in the
efficacy trials is considered sufficient to provide an
adequate pre-marketing safety database, and to              Conflict of interest statements. A.W. has participated in meetings
exclude excessive immunogenicity. Treatment-naı¨ ve         sponsored by Roche. A.M. has participated in meetings sponsored
                                                            by Roche, Janssen-Cilag and Amgen.
patients (or patients who have not received EPO
treatment for at least 3 months) with renal anaemia
are recommended as the target population, as they
provide the most sensitive model. As ever, a rigorous
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v20                                                                                                                A. Wiecek and A. Mikhail
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