EU

Number of Biosimilars Available

Country Spotlight: EU

The European Union is a politico-economic union of 28 member states: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Italy, Ireland, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, Romania, Spain, Slovakia, Slovenia, Sweden and the United Kingdom.

The European Medicines Agency (EMA) is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the EU.

Biosimilars Available

As of April 2016, there are 14 biosimilars approved for use in the EU:[1][2]

Two medicines used to treat anemia in patients with chronic kidney failure or anemia due to chemotherapy (epoetin alfa and epoetin zeta, marketed regionally under 5 different brand names)
Four medicines used treat a low white blood cell count due to chemotherapy, HIV or chronic conditions that cause a low white blood cell count; or to mobilize stem cells for transplantation (filgrastim, marketed regionally under 6 different brand names)
Two medicines used treat a low white blood cell count due to chemotherapy (filgrastim)
Insulin used to treat diabetes (insulin glargine)
Two medicines used for in vitro fertilization (follitropin alfa)
A growth hormone used to treat patients with growth deficiencies (somatropin)
A medicine used to treat Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis Ulcerative Colitis, and Crohn’s Disease, (infliximab, marketed regionally under two different brand names)
A medicine used to treat Axial Spondyloarthritis, Psoriatic arthritis, Plaque Psoriasis and Rheumatoid Arthritis (entanercept)

Score Overview

EU is Fully Compliant.

The overall score for the EU is 3.87/5. This means the EU guidance is partially or fully compliant with the WHO in most areas, in a few areas exceeds the WHO standards, and in some areas do not meet the WHO standards.

The graph below shows individual scores by each of the 28 components of biosimilar policy

There are seven areas where the EMA is not as specific as the WHO, being either non-compliant, minimally compliant, or partially compliant with the WHO biosimilar policy.

Gaps

Gap 1

Scope:

The EMA does not mention that DNA-derived therapeutic proteins are in scope, or that the biologics should be well established or well characterized. Vaccines can be considered for approval through the biosimilar pathway in the EU, while they are specifically excluded in the WHO guidances.

Gap 2

Reference Product:

When comparing the biosimilar to the original medicine, the EMA guidances do not specify that the same host cell should be used to produce the medicine.

Gap 3

Quality/Analytical, Biological Analysis:

The EMA guideline states that a comparability exercise should asses the biological properties of the biosimilar and the original biologic, not that this is a necessary step. .

Gap 4

Quality/Analytical, Immunological Analysis:

The EMA does not provide as much detail as WHO regarding how to compare immunogenicity between the biologic and the biosimilar

Gap 5

Quality/Analytical, Stability Studies:

The EMA does not require head to head studies to evaluate the stability of the biosimilar as compared with the original biologic

Gap 6

Naming:

When considering how to name biosimilar products such that clear product identification is possible, the EMA do not provide an appropriate level of specificity.

Gap 7

Labeling:

The EMA does not require biosimilar manufacturers to include the same level of transparency in the product label as the WHO.

Overall country score as compared to peers

History of Policy

The EMA were the first region to develop overarching biosimilar guidances in 2004, which were formally adopted in 2005. These have been updated and revised, with the most recent versions becoming effective in 2015. Additional guidelines have also been developed tackling specific issues related to biosimilar approval.

Many other countries have relied heavily on the EU guidances as a template for the development of their own biosimilar policies, eg Japan, or even adopted them wholesale, eg Australia.

Policy Guidelines

Overarching Guidelines

This guideline outlines general principles for demonstrating biosimilarity
First issued June 2004; Most recent update April 2015

This guideline gives advice on the quality requirements after a change occurs in the manufacturing process
First issued February 2006; Most recent update December 2014

This guideline describes the non-clinical and clinical requirements for demonstrating biosimilarity
First issued February 2006; Most recent update July 2015

Specific Biosimilar Guidances

Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use

This guideline addresses issues related to the unwanted effects on the immune system of monoclonal antibodies (mAbs) intended for clinical use.
First issued December 2012; Most recent update December 2012

Immunogenicity assessment of biotechnology-derived therapeutic proteins

This is a draft guidance that contains a list of issues to be considered when assessing the possible effects that biosimilars can have on a patient’s immune system
First issued December 2007; Most recent update October 2015 (consultation period for the update ended Jan 2016)

Comparability of biotechnology-derived medicinal products after a change in the manufacturing process – non-clinical and clinical issues

This guideline gives advice on the non-clinical and clinical requirements after a change occurs in the manufacturing process
First issued December 2003; Most recent update November 2007

Medicine Specific Guidances

These guidelines describe the non-clinical and clinical requirements for demonstrating biosimilarity for specific medicines

First issued September 2013; Most recent update September 2013

First issued September 2013; Most recent update September 2013

First issued December 2012; Most recent update December 2012

First issued September 2010; Most recent update September 2010

Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues – Guidance on similar medicinal products containing recombinant erythropoietins

First issued July 2006; Most recent update July 2006

Non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight heparins

First issued July 2013; Most recent update July 2013

First issued October 2009; Most recent update October 2009

Non-clinical and clinical development of similar medicinal products containing recombinant interferon alpha

First issued April 2009; Most recent update April 2009

Revision of the guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant granulocyte-colony stimulating factor

First issued July 2015; Most recent update July 2015

Annex to guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues – Guidance on biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor

First issued July 2006; Most recent update July 2006

First issued July 2006; Most recent update July 2006

First issued July 2006; Most recent update July 2006

Revision of the guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues

First issued September 2015; Most recent update September 2015
Note: date of first issue refers to the date the guideline received final approval from the Committee for Medicinal Products for Human Use. Most recent update refers to the date the most recent version of the guideline came into effect.

Side by side comparison of each of the score components

For each of the 28 components of biosimilar policy evaluated, the specific wording in the FDA's biosimilar policy is listed, alongside the accompanying wording in the WHO policy (shown in the blue box).

Scope

[§ 3.0] Well-established and well-characterized biotherapeutic products such as DNA-derived therapeutic proteins. A well-established biotherapeutic is one that has been marketed for a suitable period of time with proven quality, safety, and efficacy.

Excludes vaccines, plasma-derived products, and their recombinant analogues.

1/2: Minimally Compliant. No mention of cell culture or DNA-derived process is a significant deficiency. No mention of “Well-established and well-characterized..” WHO standards specifically “Excludes vaccines, plasma-derived products, and their recombinant analogues.” while this EU standard allows for consideration

[§§ 2.1, 3.3-3.5 in 2a] In principle, the concept of a biosimilar is applicable to any biological medicinal product. However, in practice, the success of such a development approach will depend on the ability to characterize the product and therefore to demonstrate the similar nature of the concerned products.

Vaccines and allergen products are considered on a case-by-case basis. Blood or plasma-derived products and their recombinant alternatives cannot be approved based on a reduced application. Biosimilar versions of gene and cell therapy medicinal products will be considered in the future.

Concept of Biosimilarity

[§ 4] A biosimilar is a biotherapeutic product that is similar in terms of quality, safety, and efficacy to an already licensed RP.

5: Exceeds. Far more descriptive and restrictive than WHO standard.

[§ 2.2 in 2a] The active substance of the biosimilar must be similar in molecular and biological terms to the active substance of the Reference Product.

[§ 1 in 2c] An extensive comparability exercise with the Reference Product is required to demonstrate that the biosimilar has a similar profile in terms of quality, safety and efficacy to the Reference Product. A comparison of the biosimilar to a publicly available standard is not sufficient for the purpose of demonstrating biosimilarity.

[§ 5.2 in 2c] For recombinant proteins, the aim of the biosimilar comparability exercise is to demonstrate that the biosimilar product and the Reference Product are similar at the level of the finished product. Differences that may confer a safety advantage should be explained but are unlikely to preclude biosimilarity.

There is no requirement for re-demonstration of biosimilarity after a biosimilar is approved.

[§ 3.1 in 2e] A draft guideline states that changes intended to improve efficacy are not compatible with the biosimilarity approach.

[§ 3.3 in 2e] A draft guideline states that differences between a proposed biosimilar and the Reference Product that could give the proposed biosimilar a safety advantage (e.g., lower levels of impurities or lower immunogenicity) should be explained, but may not preclude biosimilarity.

Reference Product

[§ 7.0] The same RP should be used throughout the entire comparability exercise and it must be approved in the country/region in question (or, where the licensing country lacks an approved RP, approved and widely marketed in another jurisdiction with a well-established regulatory framework for, and experience in evaluation and post-market surveillance of, biotherapeutics).

[§ 8.1] As a general rule, the biosimilar product should be expressed and produced in the same host cell type as the RP. The applicant should determine the potential impact of changing the host cell on product quality, safety, and efficacy based on available evidence from public information and experience with previous use of the RP. The rationale for accepting a difference in host cell must be justified based upon sound science and clinical experience with the biosimilar or the RP.

3: Partially Compliant. Does not specifically address the WHO standard that the biosimilar product should be expressed and produced in the same host cell type as the Reference Product.

[§§ 2.2, 3.1 in 2a and 1 in 2c] There may be only one Reference Product; it must be approved in the Community on basis of a complete dossier; the same Reference Product should be used throughout the comparability program (quality, safety, and efficacy); and data from products authorized outside the Community may provide only supportive information.

[§ 5.1 in 2c] An applicant cannot use a publicly available reference standard as an Reference Product.

For the analytical comparability exercise, an applicant should use multiple batches of the Reference Product. Where several strengths or presentations are available, an applicant should justify its selection.

[§ 3.2 in 2e] A draft guideline states that an applicant may compare its biosimilar product with a non-EEA authorized comparator in certain clinical studies and in vivo non-clinical studies. The applicant must establish that the non-EEA authorized comparator is representative of the EEA-authorized Reference Product. The applicant should provide adequate scientific justification of the relevance of the data involving the non-EEA authorized comparator and establish an acceptable bridge to the EEA-authorized Reference Product. This bridging data should typically include data from analytical studies that compare the proposed biosimilar, the EEA-authorized Reference Product, and the non-EEA-authorized comparator, and may also include clinical PK and/or PD bridging study data for all three products.

Formulation

[§ 8.1] The biosimilar manufacturer should assemble all available knowledge of the RP concerning the formulation used. The applicant should determine the potential impact of changing the formulation on product quality, safety, and efficacy based on available evidence from public information and experience with previous use of the RP. The rationale for accepting differences must be justified based upon sound science and clinical experience with the biosimilar or the RP.

4: Fully Compliant.

[§ 4 in 2c] The applicant should demonstrate the suitability of the proposed formulation with regard to stability, compatibility, integrity, activity, and strength of the active substance. If an applicant selects a formulation different from that of the Reference Product, it should justify the formulation’s potential impact on safety and efficacy. Formulation studies should demonstrate the suitability of the formulation, regardless of the formulation selected.

Route of Administration

[§ 5.0 ] Same as that of the RP.

4: Fully Compliant. Exceeds in that the element allows for justifiable variation.

[§ 2.2 in 2a] The route of administration of the biosimilar should be the same as that of the Reference Product. When the route of administration is not the same, additional data in the context of the comparability exercise should be provided. Any differences between the biosimilar and the Reference Product will have to be justified by appropriate studies on a case-by-case basis.

[§ 3.1 in 2e] A draft guideline states that the biosimilar’s route of administration should be the same as that of the Reference Product.

Dosage Form And Strength

[§ 5.0] Dosage form should be the same as that of the RP. Strength is not addressed.

[§ 8.1] The biosimilar manufacturer should assemble all available knowledge of the RP concerning the type of container closure system used. The applicant should determine the potential impact of changing the container closure on product quality, safety, and efficacy based on available evidence from public information and experience with previous use of the RP. The rationale for accepting a difference in container closure must be justified based upon sound science and clinical experience with the biosimilar or the RP.

4: Fully Compliant.

[§ 2.2 in 2a] The pharmaceutical form and strength of a biosimilar should be same as those of the Reference Product. When the pharmaceutical form or strength is not the same, additional data in the context of the comparability exercise should be provided. Any differences between the biosimilar and the Reference Product will have to be justified by appropriate studies on a case-by-case basis.

[§ 4 in 2c] If a container/closure system different from that of the RP is selected, its potential impact on safety and efficacy should be appropriately justified.

[§ 5.3.5 in 2c] An applicant should confirm that the biosimilar and the Reference Product have “comparable strength.”

[§ 3.1 in 2e] A draft guideline states that the biosimilar’s posology should be the same as that of the Reference Product.

General Considerations

[§ 8] The application must contain a full quality dossier for both the drug substance and the drug product.

To evaluate comparability, the manufacturer should carry out a comprehensive physicochemical and biological characterization of the biosimilar in head-to-head comparisons with the RP. All aspects of product quality and heterogeneity should be assessed.

[§ 5] Development of the biosimilar involves a stepwise approach starting with characterization and evaluation of quality attributes. Differences should always be explained and justified and may require additional data.

[§ 8.2] Investigation of differences between the biosimilar and the RP should be based on knowledge of the relationship between quality attributes and clinical activity of the RP and related products, the clinical history of the RP, and lot-to-lot differences of commercial lots of the RP.

3/4: Partially/Fully Compliant. Wording of standard implies a less strict interpretation than WHO’s intent.

[§ 4.2 in 2b] For recombinant proteins, usually comparative clinical trials are necessary to demonstrate clinical comparability.

The clinical requirements depend on the existing knowledge about the Reference Product and the claimed therapeutic indication(s). Available product/disease specific guidelines should be followed when appropriate.

The clinical comparability exercise is a stepwise procedure beginning with PK and PD followed by clinical efficacy and safety trial(s), or, in certain cases, PK/PD studies for demonstrating clinical comparability.

[§ 1 in 2f] A draft guideline states that the nature and complexity of the Reference Product affects the extent of clinical studies. Differences observed in the physicochemical and biological analyses, the mode of action of the active substance, and the pathogenic mechanisms of the relevant disease(s) will guide the planning of clinical studies.

Isolation of Drug Substance

[§ 8] Methods used to isolate RP drug substance for characterization must be justified and demonstrated to be appropriate. Studies must be carried out to demonstrate that product heterogeneity and relevant attributes of the active moiety are not affected by the isolation process.

4: Fully Compliant.

[§ 5.3 in 2c] For recombinant proteins, for some analytical techniques, a direct or side-by-side analysis of the biosimilar and the Reference Product may not be feasible or may provide limited information (e.g., due to the low concentration of active substance and/or the presence of interfering excipients). In those cases, applicants could prepare samples from the finished product (e.g., using extraction, concentration, and/or other suitable techniques). .

Physicochemical Analysis

[§ 8.2.1] The comparative physicochemical characterization should include the determination of primary and higher order structure and other biophysical properties using appropriate analytical methods (e.g. mass spectrometry, NMR).

The RP and the biosimilar are likely to contain a mixture of post-translationally modified forms, and appropriate efforts should be made to investigate, identify, and quantify these forms.

5: Exceeds. Significantly more descriptive and specific.

[§ 5.3.1 in 2c] The physicochemical characterization program for recombinant proteins includes determination of composition, physical properties, and primary and higher order structures of the biosimilar.

The primary amino acid sequence of the biosimilar and the Reference Product should be the same. Applicants should compare N- and C-terminal amino acid sequences, free SH groups, and disulfide bridges. Applicants should justify (with respect to the micro-heterogeneous pattern of the RP) any detected differences between the biosimilar and the Reference Product.

Post-translational modifications should be appropriately characterized. The carbohydrate profile, site-specific glycosylation patterns, and site occupancy should be compared. The presence of glycosylation structures or variants not observed in the Reference Product may raise concerns and require appropriate justification.

Biological and Immunological Analysis

Biological

[§ 8.2.2] Comparative evaluation with a biological assay complements the physicochemical analyses by confirming the correct higher order structure of the molecule.

Ideally, the biological assay will reflect the understood MoA of the protein and will thus serve as a link to clinical activity.

The use of a relevant biological assay(s) with appropriate precision and accuracy provides an important means of confirming that a significant functional difference does not exist between the biosimilar and the RP.

Immunological

[§ 8.2.3] When immunochemical properties are part of the characterization (e.g., for antibody-based products), the manufacturer should confirm that the biosimilar is comparable to the RP in terms of specificity, affinity, binding kinetics, and Fc functional activity, where relevant.

Biological – 3: Partially Compliant. The use of the word “should” seems counter to the intent of the WHO standard.

Immunological: - 3: Partially Compliant. WHO standards are more specific.

Biological
[§ 5.2.3 in 2c] For recombinant proteins, the comparability exercise should assess biological properties of the biosimilar and the Reference Product. Applicants should consider using biological assays that involve different and complementary approaches to measure biological activity, as appropriate. Applicants should use biological assays that are sensitive, specific, and sufficiently discriminatory.

Immunological
[§ 5.3.3 in 2c] In the case of monoclonal antibodies or related substances, immunological properties of the two products should be fully compared.

Impurities

[§ 8.2.4] It is recognized that the comparison of the impurity profiles between the biosimilar and the RP will be generally difficult. Nevertheless, process- and product-related impurities should be identified, quantified by state-of-the-art technology, and compared between the biosimilar and the RP. If significant differences are observed in the impurity profiles, their potential impact on efficacy and safety, including immunogenicity, should be evaluated.

5: Exceeds. Significantly specific.

[§ 5.2 in 2c] For recombinant proteins, it is preferable to rely on purification processes to remove impurities rather than to establish a preclinical testing program for their qualification. Differences that may confer a safety advantage (e.g. lower levels of impurities) should be explained but are unlikely to preclude biosimilarity.

[§ 5.3.4 in 2c] Purity and impurity profiles of the biosimilar and the Reference Product should be assessed qualitatively and quantitatively by a combination of orthogonal and state-of-the-art methods. These comparisons should take into account specific degradation pathways and potential post-translational modifications.

Process-related impurities are expected to differ qualitatively from one process to another, and therefore the qualitative comparison of these parameters may not be relevant in the comparability exercise. Applicants should identify, document, and justify potential risks related to these impurities.

Stability Studies

[§ 8.5] Head-to-head accelerated stability studies will be of value in determining the similarity of the products because they can reveal otherwise-hidden properties of a product that warrant additional evaluation. They are also important for identifying the degradation pathways of a protein product.

2/3: Partially Compliant. WHO standard calls for head-to head studies while §6 in 2c such studies are not required.

[§ 4 in 2c] For recombinant proteins, applicants should determine the stability of the biosimilar according to ICH Q5C. Stability claims must be supported by data and cannot be extrapolated from the Reference Product.

[§ 5.3.4 in 2c] Comparison of relevant quality attributes, tested at selected time points and storage conditions (e.g. accelerated or stress conditions), may support the similarity of the degradation pathways of the Reference Product and the biosimilar.

[§ 6 in 2c] Applicants should justify the biosimilar’s shelf life with full stability data. Comparative real-time, real-condition stability studies between the biosimilar and the Reference Product are not required.

Specifications

[§ 8.3] Specifications should capture and control important quality attributes known for the RP. Their setting should be based on the experience with the biosimilar and the results of the comparability evaluation, but should not be wider than the range of variability of the RP unless justified.

Specifications should be set as described in established guidelines and monographs, where these exist. Pharmacopoeial monographs may only provide a minimum set of requirements for a particular product, and additional test parameters may be necessary

3/4: Partial/Fully Compliant: Element could be fully compliant depending upon the interpretation of specifications contained in ICH Q6B. Specifications appear to qualify this element for a FULLY, depending on the in-country interpretation. Specifications are presumed to be based on an Reference Product.

[§ 6 in 2c] Applicants should select tests to be included in the specifications (or control strategy) for both the drug substance and the drug product as described in ICH Q6B. Applicants should describe the rationale used to establish the proposed range of acceptance criteria for routine testing.

General

[§§ 9.1, 9.2] Nonclinical studies should use the final formulation intended for clinical use unless otherwise justified; the nonclinical evaluation encompasses a broad spectrum of PD, PK, and toxicity studies (per ICH S6); the amount of additional nonclinical data for safety and efficacy is dependent on product-specific factors (for example, quality, unknown or poorly understand MoA, significant toxicity, and/or narrow therapeutic index).

4: Fully Compliant. “Response” implies data available to assess safety and efficacy. Final formulation is implied.

[§ 4.1 in 2b] Nonclinical studies for biosimilar versions of recombinant proteins should be comparative in nature and designed to detect differences in response between the biosimilar and the Reference Product (not just to detect the response in the biosimilar). Nonclinical programs should be tailored on a case-by-case basis and fully justified.

[§ 1 in 2f] A draft guideline states that the nature and complexity of the Reference Product affects the extent of the nonclinical studies. Differences observed in the physicochemical and biological analyses, the mode of action of the active substance, and the pathogenic mechanisms of the relevant disease(s) should guide the planning of nonclinical studies.

Pharmacology

[§ 9.2] In vitro studies: Assays like receptor-binding studies or cell-based assays should normally be conducted to establish comparability of PD activity.

In vivo studies: Animal studies should be designed to maximize information obtained; be conducted in relevant species (shown to possess PD and/or toxicological activity); and employ state-of-the-art technology. In vivo studies may not be needed if highly reliable in vitro assays that reflect clinically relevant PD activity of the RP are available.

5: Exceeds. EU standard specifies that the in vitro assays used are predictive of in vivo behavior.

[§ 4.1 in 2b] For recombinant proteins:

In vitro studies: Assays like receptor-binding studies or cell-based assays should normally be conducted to establish comparability in reactivity and likely causative factors if comparability cannot be established.

In vivo studies: Comparative in vivo studies should be conducted in a relevant animal species.

[§ 4.1 in 2f] In vitro studies: A draft guideline states that comparative studies could include relevant assays on binding to target(s) known to be involved in, and on signal transduction and functional activity/viability of cells known to be of relevance for, the pharmaco-toxicological effects of the Reference Product. The studies should evaluate parameters sensitive enough to detect differences. The applicant should justify that the in vitro assays used are predictive of in vivo behavior.

[§§ 4.2, 4.3 in 2f] In vivo: A draft guideline states that in vivo studies may be necessary in some cases, provided that a relevant species or design is available. A number of factors should be considered when determining whether in vivo studies are needed.

If an in vivo study is necessary, the principles of the 3Rs (replacement, refinement, reduction) should be considered when designing it. For safety studies a flexible approach should be considered, in particular if non-human primates are the only relevant species. The conduct of standard repeated dose toxicity studies in non-human primates or conduct of toxicity studies in non-relevant species usually is not recommended.

Toxicology

[§ 9.2] Comparative repeat-dose toxicity in relevant species (including TK measurements and antibody responses); local tolerance may need to be evaluated depending on the route of administration.

Safety pharmacology, reproductive toxicology, genotoxicity, and carcinogenicity studies are generally not needed unless cause for concern (based on repeat dose toxicity study or local tolerance study, for example).

4: Fully Compliant.

[§ 4.1 in 2b] For recombinant proteins, at least one repeat-dose toxicity study should be conducted in relevant animal species (with TK measurements) of sufficient duration to allow detection of relevant differences in toxicity and/or immunogenicity between the biosimilar and the Reference Product.

Safety pharmacology, reproduction toxicity, mutagenicity, and carcinogenicity studies are not required unless indicated from the results of repeat dose studies.

[§ 4.2 in 2f] A draft guideline indicates that animal studies evaluating toxicity may not be necessary in all cases.

PK and PD

[§ 10] Clinical studies should be designed to demonstrate comparable safety and efficacy of the biosimilar to the RP and therefore need to employ strategies that are sensitive enough to detect relevant differences. The comparability exercise is a stepwise procedure that should begin with PK and PD studies followed by the pivotal clinical trials.

If any relevant differences between the biosimilar and the RP are detected, the reasons need to be explored and justified. If this is not possible, the new product may not qualify as a biosimilar and a full licensing application should be considered.

5: Exceeds. Far more specific than WHO standards.

[§ 4.2 in 2b] For recombinant proteins, PK studies should evaluate not just bioavailability, but also clearance and elimination half-life.

The choice of PK study design should be justified, and the ordinary cross-over design is not appropriate for proteins with a long half-life or for which formation of anti-drug antibodies is likely.

The PD effect should be compared in a population where possible differences can best be observed.

Combined PK/PD studies should be conducted in the steep part of the dose-response curve.

The PK acceptance criteria used in standard clinical comparability studies, initially developed for chemically derived, orally administered products, may not be appropriate. Clinical comparability limits should be defined and justified prior to conducting the study.

[§ 5.1 in 2f] A draft guideline states that for the demonstration of comparable PK, it is advisable to select the most sensitive test model. A parallel group design may be necessary with substances with a long half-life and high risk of immunogenicity. If the Reference Product can be administered both intravenously and subcutaneously, it is possible to waive the evaluation of intravenous administration if comparability in both absorption and elimination has been demonstrated for the subcutaneous route.

Efficacy Assessment

[§ 10.1] The PK profile should always be investigated. This is best achieved with single-dose, cross-over studies in a homogenous study population using a dose where the sensitivity to detect differences is largest. Where there are dose and time-dependent pharmacokinetics, it may be necessary to perform a comparative multi-dose study.

The traditional equivalence range is often used. If this range is not met, the biosimilar may still be considered similar with sufficient evidence from other comparisons.

[§ 10.2] PD studies may be advisable prior to efficacy and safety trials if differences of unknown relevance have been detected in PK studies. In many cases, PD parameters are investigated in the context of combined PK/PD studies.

5: Exceeds. Specificity, scope, and criteria exceed WHO’s.

[§ 4.2 in 2b] Comparative efficacy clinical trials will usually be necessary for recombinant proteins. Clinical comparability margins should be pre-specified and justified primarily on clinical grounds. If a clinical comparability trial design is not feasible, other designs should be explored and discussed with competent authorities.

Confirmatory PK/PD may be used in lieu of efficacy trials for recombinant proteins, provided there is sufficient knowledge of the PK/PD profiles of the RP and dose-response relationship, at least one PD marker is accepted as a surrogate marker for efficacy, and the relationship between dose/exposure and that marker is well-known.

[§ 5.3 in 2f] A draft guideline states that the study population should be representative of approved therapeutic indication(s) of the RP and be sensitive for detecting potential differences between the products.

[§ 5.3.1 in 2f] A draft guideline states that in general, an equivalence design should be used, although the use of a non-inferiority design may be acceptable if justified on the basis of a strong scientific rationale.

[§§ 3.3 in 2e and 5.2 in 2f] Draft guidelines state that in specific circumstances, such as for structurally simpler biologics, a comparative clinical efficacy study may not be necessary if: (1) the similarity of physicochemical characteristics and biological activity/potency of the biosimilar and the Reference Product can be convincingly shown; and (2) similar efficacy and safety can be clearly deduced from these data and comparative PK data. This approach would need to be supported by additional data, such as in vitro and/or clinical PD data from a comprehensive comparative PD “fingerprint” approach.

[§ 5.3.2 in 2f] A draft guideline states that if clinical trials with the Reference Product have already demonstrated the correlation between “hard” clinical endpoints (recommended in guidelines) and other clinical/PD endpoints that are sensitive to detect differences, it is not necessary to use the same primary efficacy endpoints as those used in the Reference Product’s marketing authorization application. The applicant should include some common endpoints, however, to facilitate comparisons to the Reference Product’s clinical trials.

Safety

[§ 10.3] Usually, clinical trials are required to demonstrate similar efficacy. Confirmatory PK/PD may be used in lieu of efficacy trials provided there is sufficient knowledge of the PK/PD profile of the RP, at least one PD marker has a well-established relationship to efficacy, and the relationship between dose/exposure, the relevant PD marker, and response/efficacy of the RP is established.

[§ 10.4] Similar efficacy means similar treatment effects are achieved at the same dosages.

Similar efficacy will usually have to be shown in a controlled, adequately powered, study that is, preferably, double blind. Potential differences between the products should be investigated in a sensitive and well-established clinical model.

5: Exceeds. Specificity, scope, and criteria exceed WHO’s. Presumes that the extensive data collection from efficacy trials will be augmented to acquire safety data.

[§ 4.3 in 2b] For recombinant proteins, pre-licensing safety data are required from a sufficient number of patients to address the adverse effect profiles of the test. A comparison of the type, severity, and frequency of adverse reactions between the products should be done.

[§ 5.4 in 2f] A draft guideline states that an application should include an evaluation of the specific risks anticipated for the biosimilar, including a description of possible safety concerns related to infusion-related reactions and immunogenicity of the biosimilar that may result from a manufacturing process different from that of the Reference Product.

Immunogenicity

[§ 10.5] Safety data should be obtained in a sufficient number of patients to provide a comparison of type, frequency, and severity of adverse events. Safety data from the efficacy trials may be sufficient for this purpose (or may need to be extended), but in any case additional monitoring is usually necessary after approval.

5: Exceeds. Criteria more specific and broader than WHO.

[§ 4.4 in 2b] For recombinant proteins, immunogenicity of a biosimilar must always be investigated and should include data from a sufficient number of patients to characterize the variability in antibody response.

The assessment requires an optimal antibody testing strategy, characterization of the observed immune response, and evaluation of correlation of antibodies to PK and PD relevant to safety and efficacy.

Immunogenicity risks in different indications should be considered separately.

Long term results of monitoring of antibodies at pre-determined intervals are required. In the case of chronic administration, one-year follow up data are required pre-licensing.

The applicant should consider antibodies to process-related impurities.

If a different immune response is observed compared with the Reference Product, further analyses to characterize the antibodies and their implications to safety, efficacy, and PK are required with special consideration to the possibility of interaction with endogenous protein.

[§ 5.4 in 2f] A draft guideline states that duration of the immunogenicity study and follow-up should be justified on a case-by-case basis.

A proposed biosimilar with higher immunogenicity as compared to the Reference Product may affect the benefit/risk analysis and raise questions about biosimilarity, but lower immunogenicity would not preclude approval as a biosimilar.

Extrapolation of Indications

[§ 10.6] Immunogenicity should always be investigated in humans prior to authorization, because animal data are usually not predictive and because it could affect PK, PD, or safety. Generally, the data from a comparative efficacy trial will be sufficient prior to market authorization, subject to appropriate post-market pharmacovigilance for rare adverse events or where clinically meaningful or serious antibody development has been encountered in the RP or substance class.

In the case of chronic administration, one year of data prior to market authorization is usually appropriate.

[§ 10.6] Antibody assays need to be validated for their purpose. Detected antibodies need to be characterized for their clinical implications with special attention to the possibility of interaction with endogenous protein.

3/4: Partially / Fully Compliant. Lacks WHO criteria; interpretation of guidance will determine compliance level.

[§ 1 in 2b] For recombinant proteins, in certain cases, it may be possible to extrapolate therapeutic similarity to other indications. Justification will depend on clinical experience, available literature, and whether the same MoA or receptor is involved in both indications. Possible safety issues in different subpopulations also should be addressed.

[§ 6 in 2f] A draft guideline states that if there is evidence that different active sites of the Reference Product or different receptors of the target cells are involved in different indications or that the safety profile of the Reference Product differs between indications, additional data may be needed to justify extrapolation. For extrapolation of safety, the applicant should consider patient-related factors, such as different co-medications, co-morbidities, and immunological status, and disease-related factors. The extent of data required to justify extrapolation should be considered in the light of the totality of evidence derived from the biosimilar comparability exercise and the potential remaining uncertainties.

Risk Management Plans

[§ 10.7] Extrapolation to other approved indications of the RP may be possible if all of the following conditions are met: (1) a sensitive clinical test model has been used that is able to detect potential differences between the products; (2) the clinically relevant MoA and/or receptors are the same (or, if the MoA is different or not known, a strong scientific rationale and additional data will be needed); (3) safety and immunogenicity of the biosimilar have been characterized and there are no special safety issues expected with the extrapolated indication; and (4) if the efficacy trial used a non-inferiority study design and demonstrated acceptable safety and efficacy of the biosimilar compared to the RP, the applicant should provide convincing arguments that this finding can be applied to the extrapolated indications.

If these prerequisites for extrapolation of efficacy and safety data of the biosimilar to other indication(s) of the RP are not fulfilled, the manufacturer will need to submit its own clinical data to support the desired indication(s).

5: Exceeds. Cites monitoring efficacy and implies traceability.

[§ 2.1 in 2a] In order to support PV monitoring, the specific medicinal product given to the patient should be clearly identified.

[§ 4.3 in 2b] For recombinant proteins, data from pre-authorization studies normally are insufficient to identify all potential differences, so clinical safety must be monitored closely post-approval, including continued benefit-risk assessment.

The dossier should include a risk specification and PV plan including possible safety issues related to the manufacturing changes and risks identified during development. Monitoring imposed on the Reference Product or product class should be taken into consideration.

[§ 4.4 in 2b] The sponsor needs to encourage reporting of adverse events relevant to immunogenicity, including loss of efficacy.

[§ 7 in 2f] A draft guideline states that risk minimization activities in place for the Reference Product should be included in the risk management program of the biosimilar. Applicants should follow developments with regard to switching and interchangeability of medicines and consider these practices when developing the risk management plan. Available data on switching should be carefully assessed during the review of adverse reaction reports.

Interchangeability

[§ 11] Data from pre-authorization clinical studies are usually too limited to identify all potential unwanted effects of a biosimilar, and in particular, rare adverse events.

Therefore, further close monitoring of the clinical safety of these products in all approved indications and continued benefit-risk assessment is necessary in the post-market phase.

A safety specification and PV plan are required at the time of submission, describing safety issues for the RP, the class, and/or the biosimilar.

Any special safety monitoring imposed on the RP or product class should be incorporated into the PV plan for the biosimilar, unless there is a compelling justification not to do so.

The regional authority should provide a framework establishing the ability to ensure specific identification of the biosimilar (i.e., traceability). There should be a legal framework adequate to identify any biotherapeutic marketed in its territory that is the subject of adverse event reports.

3/4: Partially / Fully Compliant. Does not reference a unique brand name; otherwise compliant.

In the EU, interchangeability and substitution practices are determined at the Member State level and therefore this topic is not directly addressed in the EMA guidance.

[§ 2.1 of 2a] Biosimilars are not generic medicinal products.

[2d] Because biosimilars and Reference Products are similar but not identical, the decision to treat a patient with a Reference Product or a biosimilar should be taken following the opinion of a qualified healthcare professional.

Naming

Not addressed specifically. To be determined by national authorities.

[§ 6, bullet e] Biosimilars “are not generic medicines; and many characteristics associated with [that] authorization process generally do not apply.”

[§ 12] The biosimilar should be clearly identifiable by a unique brand name, and the prescribing information should be as similar as possible to that of the RP except for product-specific aspects such as different excipients.

Note: Naming and interchangeability should be treated as separate issues. WHO has recommended a generic name plus numbering system. Naming, per se, is not about the basic science of interchangeability.

1/2: Minimally Compliant. Lacks the specificity of the WHO’s INN standard.

Not addressed in a guideline.

[§ 2.1 in 2a] In order to support PV monitoring, the specific medicinal product given to the patient should be clearly identified.

[2d] The name, appearance, and packaging of a biosimilar medicine differ from those of the Reference Product.

Labeling

[§ 12.0] A biosimilar should be clearly identifiable by a unique brand name. Where an international non-proprietary name (INN) is defined, it should be stated. The WHO’s policy on INNs should be followed. The provision of a lot number is essential and critical for traceability.

[Note: In July 2014, the WHO issued a proposal for unique biologic identifiers (BQs) that could be added to the INNs of biologics, whether innovative or biosimilar. See INN Working Doc. 14.342 (July 2014).]

2/3: Partially Compliant. WHO’s standard is broader.

[2d] A biosimilar may contain different inactive ingredients. As for all medicines where precautions are necessary because of any inactive ingredient, these precautions will be described both on the label and in the package leaflet.

Considerations for Quality by Design

[§ 12] The prescribing information for the biosimilar should be as similar as possible to that of the RP, except for product-specific aspects, such as different excipient(s). This is particularly important for posology and safety-related information, including contraindications, warnings, and adverse events.

If the biosimilar has fewer indications than the RP, the related text in various sections may be omitted unless it is considered important to inform doctors and patients about certain risks (e.g. because of potential off-label use). In such cases it should be clearly stated in the prescribing information that the biosimilar is not indicated for use in the specific indication(s) and the reasons why.

The national regulatory authority may choose to mention the biosimilar nature of the product and the studies that have been performed with the biosimilar, including the specific RP, in the product information.

The national regulatory authority may choose to include instructions for the prescribing physician on how to use biosimilar products.

4: Fully Compliant.

For recombinant proteins:

[§ 4.1 in 2b] Consideration should be given to use of emerging nonclinical technologies (e.g., real-time binding assays for in vitro and genomic/proteomic microarray for in vivo to detect minor changes in biological response).

[§§ 1, 4 in 2c] Biosimilars are manufactured and controlled according to their own development, using state-of-the-art approaches and taking into account state-of–the-art information on manufacturing processes and consequences on product characteristics. Biosimilars are defined by the molecular composition of the active substance resulting from its manufacturing process. Applicants should appropriately design the manufacturing process to achieve the biosimilar’s quality target product profile.

[§ 5.3 in 2c] Applicants should apply extensive state-of-the-art analytical characterization studies to the biosimilar and the Reference Product in parallel, to demonstrate comparable quality.

[§ 5.3.4 in 2c] Applicants should use orthogonal and state-of-the-art methods to identify and compare product-related substances and impurities. Applicants should use state-of-the-art analytical technologies following existing guidelines and compendial requirements when evaluating process-related impurities.

Footnotes

[1] Source: http://www.biosimilarz.com/?page_id=242

[2] Source: http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe

CBPE

Number of Biosimilars Available

Country Spotlight: EU

Biosimilars Available

Score Overview

EU is Fully Compliant.

Scores by measured component

Gaps

Gap 1

Gap 2

Gap 3

Gap 4

Gap 5

Gap 6

Gap 7

Overall country score as compared to peers

History of Policy

Policy Guidelines

Side by side comparison of each of the score components

Footnotes