Japan

Number of Biosimilars Available

Country Spotlight: Japan

The Ministry of Health, Labour, and Welfare (MHLW) is a cabinet level ministry of the Japanese government. The ministry provides regulation on basic food and drug regulations. The Pharmaceuticals and Medical Devices Agency’s (PMDA) Office of Biologicals works with MHLW to review clinical trials of new drugs and biologic medicines, including biosimilars. In Japan, biosimilars are known as Follow on Biologics (FOBs).

Biosimilars Available

As of April 2016, there are 8 biosimilars approved for use in Japan [1][2]

Two medicines used to treat anemia in patients with chronic kidney failure or anemia due to chemotherapy (epoetin alfa and darbepoetin alfa)
Three 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)
Two insulin medicines used to treat diabetes (insulin glargine)
A growth hormone used to treat patients with growth deficiencies (somatropin)
A medicine used to treat Rheumatoid Arthritis, Ulcerative Colitis, and Crohn’s Disease (infliximab)

Score Overview

Japan is Partially Compliant.

The WHO guidance was compared to the relevant sections across the PMDA guidelines, resulting in an overall score for the US is 3.05/5. This means the PMDA guidelines are partially or fully compliant with WHO in many areas, and in some areas do not meet WHO standards.

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

There are 13 areas where the PMDA is not as specific as WHO, being either non-compliant, minimally compliant, or partially compliant with the WHO biosimilar policy.

Gaps

Gap 1

Dosage Form and Strength:

The PMDA does not address the type of container closure system that should be used, and how that container closure system should compare to that of the original biologic.

Gap 2

Quality/Analytical, General Considerations:

In describing the evaluation of comparability between the biologic and biosimilar, the PMDA does not specify that head to head comparisons should be made when conducting physicochemical and biological characterization.

Gap 3

Quality/Analytical, Immunological Analysis:

The PMDA do not provide as much detail or specificity as WHO regarding how to compare immunogenicity between the biologic and the biosimilar.

Gap 4

Nonclinical, General:

The PMDA is not as specific as WHO in describing the types of nonclinical studies that are required to demonstrate biosimilarity.

Gap 5

Nonclinical, Pharmacology (in vivo and in vitro):

The PMDA do not provide specificity for the in vivo and in vitro studies that are required to demonstrate biosimilarity, or what these studies are expected to demonstrate.

Gap 6

Nonclinical, Pharmacokinetics:

The PMDA do not address the need for pharmacokinetic studies.

Gap 7

Nonclinical, Toxicology:

The guideline does not provide any specificity regarding the requirements for evaluating dose toxitciy or toxicokinetic studies, simply stating they ‘may be useful’

Gap 8

Clinical, Immunogenicity:

The PMDA guideline is less specific than the WHO about how to compare immunogenicity between the biosimilar and the original biologic.

Gap 9

Indication Extrapolation:

The PMDA do not provide the same degree of detail as the WHO in describing when it is appropriate for the biosimilar to be approved for all the indications held by the original biologic, regardless of whether those indications have been studied

Gap 10

Interchangeability:

When switching between the biosimilar and original biologic, the WHO specify that the biosimilar should be clearly identifiable by a unique brand name, whereas the PMDA do not.

Gap 11

Naming:

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

Gap 12

Labeling:

The PMDA do not address what information should be included in the biosimilar product label.

Gap 13

Manufacturing and Analytical Technology:

The PMDA do not address what technology should be used to manufacture a high quality biosimilar

Overall country score as compared to peers

History of Policy

Japan developed their follow on biologics guidelines in 2009.[3] The guidelines follow the principles of the EU biosimilars guideline.

Policy Guidelines

Guideline for the Quality, Safety and Efficacy Assurance of follow-on biologics

This guideline is intended to assist those making biosimilar medicines by providing guidance on how to demonstrate that a biosimilar is comparable to an original biologic medicine for purposes of the submission of a marketing application.
First issued March 2009; Most recent update March 2009

Nonproprietary name and brand name of follow-on biologics

This guideline provides information on biosimilar naming
First issued February 2013; Most recent update February 2013

Marketing Approval Application for follow-on biologics

This guideline provides details on how to file a marketing approval application for a biosimilar
First issued March 2009; Most recent update March 2009

Questions &Answers regarding Guideline

Provides answers to frequently asked questions related to the Guideline, and its implications for those developing biologics and biosimilars.
First issued March 2010; Most recent update March 2010

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.

[§ 2.0 in 1a] (1) Recombinant proteins (including simple proteins and glycoproteins) that have been produced using microorganisms or cultured cells, have been highly purified, and can undergo characterization by means of a series of appropriate analytical procedures; (2) polypeptides and derivatives thereof; and (3) drugs containing these as constituent ingredients.

May also apply to other categories of products that have been highly purified and can undergo quality characterization (e.g., non-recombinant protein products produced using cell culture techniques or proteins and polypeptides that have been isolated from tissue or body fluids).

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.

[§ 3.0 in 1a] The reference product must be approved in Japan and be the same product throughout the development period of the biosimilar (the entire quality, nonclinical, and clinical development period).

[§ 4.1 in 1a] In the creation of cell bank systems for the manufacture of biosimilars, where the host cell of the reference product has been disclosed, it is preferable to proceed with the development using the same host cell.

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.

[§ 4.3 in 1a] The formulation of the biosimilar does not need to be identical to that of the Reference Product, provided any differences do not affect efficacy or safety.

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.

[§ 4.3 in 1a] 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.

[§ 8 in 1a] Clinical studies should generally be required for biosimilars because of the difficulty of verifying bioequivalence and quality equivalence. They may not be required, however, where data sufficient to assure bioequivalence and quality equivalence have been obtained through nonclinical PK, PD, or PK/PD studies. To the extent that clinical studies are required, the type and content of the studies will depend upon the biosimilar’s characteristics and will be determined on a case-by-case basis. A sponsor should therefore consult with the regulatory authorities regarding the proper scope of such studies for its particular biosimilar.

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 in 1a] The applicant must conduct studies comparing differences in the structural and physiochemical properties of the biosimilar and the Reference Product.

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

[§ 5 in 1a] The applicant must conduct studies comparing bioactivity, such as comparative studies of cell proliferation and differentiation, receptor-binding activity, enzyme activity, other in vitro bioactivity closely linked to clinical effects, and — in the case of glycan structures — in vivo bioactivity studies.

Immunological

[§ 5 in 1a] The applicant must conduct studies comparing immunogenicity.

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.

[§ 4.2 in 1a] Product-related and process-related impurities should be evaluated in conjunction with the efficacy of the purification process.

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.

[§ 4.4 in 1a] To determine a biosimilar’s shelf life, long-term storage testing should be conducted.

The shelf life of the biosimilar does not need to be identical to that of the Reference Product, provided any differences do not affect efficacy or safety.

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

[§ 6 in 1a] Each manufacturing process should include appropriate specifications, test procedures, and a process control method. Specifications and test procedures should be based on the results of characterization or lot analyses and should be established in accordance with ICH Q6B. If the biosimilar is listed in an official compendium (such as the Japanese Pharmacopoeia), specifications and test procedures for the biosimilar should be based on the specifications and test procedures listed in the compendium. Otherwise, supplementary specifications should be developed based on the results of the biosimilar’s characterization, clinical testing, impurity profile, bioactivity, and the like.

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).

[§ 7.0 in 1a] Prior to performing clinical studies, the biosimilar applicant must conduct nonclinical studies to verify that the product can be safely administered to humans. These nonclinical studies may be conducted with reference to ICH S6. Prior to any nonclinical studies, each biosimilar must be subjected to a full quality characterization.

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.

[§ 7.2 in 1a] The pharmacological action of the biosimilar and the Reference Product should be compared through nonclinical pharmacological studies.

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).

[§ 7.1 in 1a] Repeated dose toxicity and toxicokinetic (TK) studies may be useful.

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.

[§ 8.1 in 1a] For PK, PD, or PK/PD studies, the study population should be selected in light of the properties of the biosimilar, the Reference Product, and the target disease. The study should be conducted using the same route(s) of administration as used in the case of the Reference Product and should typically be based on the recommended dosage of the Reference Product.

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.

[§ 8.2 in 1a] In cases where high bioequivalence and quality equivalence have been demonstrated, but the combined PK, PD, or PK/PD study results show inconclusive bioequivalence or quality equivalence in terms of clinical efficacy, clinical studies should be conducted to verify efficacy for the specific indications for which approval is sought.

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.

[§ 8.3 in 1a] Even where a biosimilar’s bioequivalence and quality equivalence with regard to efficacy have been demonstrated, the safety profile of the biosimilar may differ from that of the Reference Product. Studies designed to compare efficacy may be designed also to investigate safety (adverse event types and incidence). Where the assessment of the biosimilar’s impurity profile gives rise to concerns about safety, the clinical trials should have an appropriate number of subjects to ensure adequate investigation of these concerns. Sponsors should also consider conducting repeat-dose studies for drugs administered long-term.

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.

[§ 8.3 in 1a] At an appropriate stage of clinical development, sponsors should conduct studies to evaluate immunogenicity.

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.

[§ 8.2 in 1a] If the Reference Product is approved for multiple indications, the biosimilar sponsor may be able to extrapolate study results to other indications if the biosimilar sponsor can show that a similar pharmacological result can be expected for the relevant indications. But where the MoA differs for each indication or the MoA is not clear, equivalence of efficacy with the Reference Product should be demonstrated for each indication.

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).

[§ 9 in 1a] Because information from pre-market clinical studies is generally limited and because biologics raise special concerns (especially immunogenicity issues), post-marketing surveillance of the safety profiles of biosimilars is required. The method and design of the post-marketing surveillance study and RMP for a biosimilar should be discussed with the regulatory authorities, and the plan should be submitted with the application for approval. Findings from post-marketing surveillance should be reported in a timely manner to the regulatory authorities.

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.

[§ 9 in 1a] It is vital to assure the traceability of adverse events during the respective surveillance period. Notwithstanding any switch of the Reference Product or drug with similar indications to the biosimilar, their substitution or combined application should in principle be avoided throughout the treatment period.

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.

[1b] The nonproprietary name, known as the Japanese Accepted Name (JAN), of a biosimilar is determined by applying the following formula:

JAN of the Reference Product + “[” + JAN of the Reference Product minus “rDNA,” if any + “Biosimilar” + the order number of the biosimilar product + “]”.

There is an exception to this formula, however, for biosimilars that are simple protein products. If the “essence” (including primary structure) of a biosimilar that is a simple protein is “identical” to that of the Reference Product, the biosimilar is given the same non-proprietary name as the Reference Product.

The proprietary name of a biosimilar is determined by applying the following formula:

JAN of the Reference Product without “rDNA,” if any + “BS” + dosage form + strength + company name (the company name may be in brackets if it would otherwise be confusing).

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).]

Not addressed.

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.