USA

Number of Biosimilars Available

Country Spotlight: USA

The Federal Drug Administration (FDA) is a federal agency of the United States Department of Health and Human Services, responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the United States.

Biosimilars Available

There are 2 biosimilars available, listed in FDA’s “Purple Book” *.

A replica of Amgen’s Neupogen (filgrastim), called Zarxio (filgrastim-sndz), used to treat a low white blood cell count that can occur as a result of receiving chemotherapy.
A biosimilar to Remicade (infliximab), called Inflectra (infliximab-dyyb) a medicine used to treat Rheumatoid Arthritis, Psoriatic Arthritis, Psoriasis, Ankylosing Spondylitis, Ulcerative colitis and Crohn’s disease.

The number of approved biosimilars available in the US is likely to expand rapidly over the coming months and years. As of April 2016, there are 44 open studies investigating biosimilars.[1]

Score Overview

USA is Fully Compliant.

The WHO guidance was compared to the relevant sections across the FDA guidances, resulting in an overall score for the US is 4.38/5. This means the FDA guidances are at least fully compliant with the WHO in most categories, and in many areas, exceed the WHO standards.

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

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

Gaps

Gap 1

Scope:

It does not mention that DNA-derived therapeutic proteins are in scope, or that the biologics should be well established or well characterized.

Gap 2

Reference Product:

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

Gap 3

Nonclinical, general:

The FDA guidances do not provide an adequate degree of specificity about the particular animal studies required.

Overall country score as compared to peers

History of Policy

The FDA developed their overarching biosimilar guidances in 2012, and these have been updated and revised, with the most recent versions being published in 2015. Generally speaking, FDA will publish draft guidelines which are available for public comment before a finalized version is published.

Policy Guidelines

Nonproprietary Naming of Biological Products (Draft guidance)

This draft guidance describes FDA’s current thinking on the need for biological products to bear a nonproprietary name that includes an FDA-designated suffix.
First issued August 2015; Most recent update August 2015

Labeling for Biosimilar Product (Draft guidance)

This draft guidance is intended to assist applicants in developing draft labeling for submission in applications for proposed biosimilar products.
First issued March 2016; Most recent update March 2016

Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants

This guidance provides recommendations to industry on formal meetings between the FDA and those making biosimilar medicines.
First issued March 2013; Most recent update November 2015

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

This guidance 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 February 2012; Most recent update April 2015

Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

This guidance is intended to provide recommendations on the scientific and technical information for the chemistry, manufacturing, and controls (CMC) section of a marketing application for a biosimilar.
First issued February 2012; Most recent update April 2015

Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (Draft guidance)

This draft guidance is intended to assist those making biosimilar medicines with the design and use of clinical pharmacology studies needed to demonstrate that there are no meaningful differences between a biosimilar and the original biologic medicine.
First issued May 2014; Most recent update May 2014

Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (Draft guidance)

This draft guidance is intended for those developing biologic medicines and provides information that will help the FDA determine the date of first licensure. This is important as it relates to patent expiry.
First issued August 2014; Most recent update August 2014

First issued May 2015; Most recent update May 2015

Provides answers to frequently asked questions related to the Biologics Price Competition and Innovation Act of 2009, and its implications for those developing biologics and Biosimilars
First issued February 2012; Most recent update April 2015

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.

[42 U.S.C. § 262(i)(1)] Any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptides), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound).

[§§ III, V in 6b and I, VII.A in 6c] FDA’s draft guidance documents address considerations concerning the approval and regulation of adequately characterized therapeutic protein products (that are not chemically synthesized polypeptides).

[§§ IV in 6b and A.II.1 in 6d] A protein is any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size. A chemically synthesized polypeptide is any alpha amino acid polymer that is: (1) made entirely by chemical synthesis; and (2) less than 100 amino acids in size.

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.

[42 U.S.C. § 262(i)(2)] A product is biosimilar if it is highly similar to the Reference Product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between it and the Reference Product in terms of safety, purity, and potency.

[§ VI.B in 6c] Clinically meaningful differences could include a difference between the expected range of safety, purity, and potency of the biosimilar and that of the Reference Product. Slight differences in rates of adverse events ordinarily would not be considered clinically meaningful.

[§§ II, VI.A., VI.B, VII in 6c] FDA will use a risk-based, totality-of-the-evidence approach to evaluate information submitted in support of a demonstration of biosimilarity. Applicants should use a stepwise approach in their development program (which may include a comparison of the biosimilar and Reference Product with respect to structure, function, animal toxicity, human PK and PD, clinical immunogenicity, and clinical safety and effectiveness). At each step, the applicant should evaluate whether there is residual uncertainty about the biosimilarity of the product and identify next steps to try to address it. The type and amount of analyses and testing needed will be determined on a product-specific basis.

[§§ VI.B in 6c and A.I.3 in 6d] An applicant may be able to demonstrate biosimilarity even if there are formulation or minor structural differences, provided that the differences are not clinically meaningful.

[§§ VI.A in 6b and VII.A in 6c] It is expected that the expression construct for a biosimilar will encode the same primary amino acid sequence as the Reference Product. Minor modifications, however, such as N or C terminal truncations that will not have an effect on safety, purity, or potency, may be justified.

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.

[42 U.S.C. § 262(k)(2)(A)(i)(I)] An application must demonstrate that the product is biosimilar to an Reference Product.

[42 U.S.C. § 262(i)(4)] An Reference Product is the single biological product licensed under section 351(a) of the Public Health Service Act against which a biosimilar is evaluated.

[42 U.S.C. § 262(k)(2)(A)(i)(II)] The biosimilar and Reference Product must utilize the same mechanism(s) of action (MoAs) for the condition(s) of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the MoA is known for the Reference Product.

[§ VI.G in 6b] Even when multiple approved products are on the market, the applicant must demonstrate that the product is biosimilar to a single Reference Product previously licensed by FDA.

[§§ V in 6b, V in 6c, and A.I.8 in 6d] In general, an applicant must provide information to demonstrate biosimilarity based on data comparing the biosimilar with the Reference Product. Analytical studies and at least one clinical PK study (and, if appropriate, at least one PD study) must include an adequate comparison to the Reference Product (although for certain complex biologics, a modified approach may be needed).

Under certain circumstances, however, a sponsor may seek to use data derived from animal or clinical studies comparing the biosimilar with a non-U.S.-licensed product. In that case, the applicant should provide information to establish an acceptable scientific bridge to the Reference Product. The bridge is likely to include: (1) comparative physicochemical characterization; (2) bioassays/functional assays; (3) comparative clinical and/or nonclinical PK and/or PD data; and (4) data to address any differences in formulation or primary packaging.

Issues an applicant may need to address to use a non-U.S. product include, but are not limited to: (1) the relevance of the design of the clinical program to support a demonstration of biosimilarity to the Reference Product; (2) the relationship between the license holders for the non-U.S. product and the Reference Product (including whether the non-U.S. product is manufactured in the same facility/ies as the Reference Product); (3) whether the facilities were inspected by an ICH regulator (or equivalent); (4) whether the non-U.S. product was licensed by a regulatory authority (such as an ICH authority) with standards similar to those of FDA; (5) the extent and duration of the non-U.S. product’s marketing history; and (6) the bridge between the non-U.S. product and the Reference Product.

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.

Route of Administration

[§ 5.0 ] Same as that of the RP.

[42 U.S.C. § 262(k)(2)(A)(i)(IV)] Must be the same as that of the Reference Product.

[§ A.I.5. in 6d] An applicant may obtain licensure for fewer than all routes of administration for which an injectable Reference Product is licensed. An applicant may, however, need to provide information from studies using a route of administration for which licensure is not requested but that may be more sensitive for, e.g., a comparative assessment of immunogenicity.

[§ A.I.4 in 6d] Some design differences in the delivery device or container closure system of the biosimilar may be acceptable, if adequate performance data are provided.

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.

[42 U.S.C. § 262(k)(2)(A)(i)(IV)] Must be the same as that of the Reference Product.

[§ A.I.12 in 6d] To have the same strength as its Reference Product, an injectable biosimilar should, in general, have the same total content and concentration of drug substance as the Reference Product. (For certain complex biologics, a modified approach may be needed.)

[§ A.I.4 in 6d] Some design differences in the delivery device or container closure system of the biosimilar may be acceptable, if adequate performance data are provided.

[§ A.I.6 in 6d] An applicant may obtain licensure for fewer than all “presentations (e.g., strengths, delivery device, or container closure systems)” for which the Reference Product is licensed. If an applicant seeks licensure for a particular condition of use for which the Reference Product is licensed and it corresponds to a certain presentation of the Reference Product, however, the applicant may need to seek licensure for that particular presentation.

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.

[42 U.S.C. § 262(k)(2)(A)(i)(I)(cc)] An application must include data derived from a clinical study or studies (including the assessment of immunogenicity and PK or PD) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the Reference Product is licensed and intended to be used and for which licensure is sought.

[42 U.S.C. § 262(k)(2)(A)(ii)] The Secretary may determine that these data are unnecessary.

[§§ III in 6b and VII.D in 6c] An assessment of biosimilarity ”generally” will include a clinical study or studies. The scope and magnitude of clinical studies will depend on the extent of residual uncertainty about biosimilarity after conducting structural and functional characterization and (possibly) animal studies. Safety and effectiveness concerns for the Reference Product may also affect the clinical program design. Lessening the number or narrowing the scope of clinical PK, PD, immunogenicity, or safety and effectiveness studies should be scientifically justified.

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.

[§§ VI.G in 6b and VII.A in 6c] An analytical similarity assessment should use lots that demonstrate the biosimilarity of the biosimilar used in the principal clinical trial to the Reference Product and to the proposed commercial product, and should support the biosimilarity of both the clinical material and the commercial product.

If the drug substance has been extracted from the Reference Product to assess analytical similarity, the applicant should describe the extraction procedure and provide support that the procedure does not alter product quality.

[§ VI.H in 6b] Characterization studies should be performed on the most downstream intermediate best suited for the analytical procedures used. Characterization studies are often performed on bulk drug substance, but if the bulk drug substance is reformulated and/or exposed to new materials in the finished dosage form, the impact of these changes should be considered.

If the finished drug product is best suited for a particular analysis, the characterization should involve a comparison with the finished Reference Product. The acceptability of any differences should be evaluated and supported. Different excipients should be supported by toxicology data. Because differences in excipients may affect product degradation and/or clinical performance, they are among the factors that may affect whether subsequent clinical studies may take a selective and targeted approach.

[§ VII.A in 6c] Applicants should analyze the finished dosage form of multiple lots of the biosimilar and Reference Product to assess excipients and any formulation effect on purity, product- and process-related impurities, and stability.

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.

[§ V in 6b] Extensive, robust comparative physicochemical studies should be performed. Physicochemical and functional characterization studies should be sufficient to establish relevant quality attributes including those that define identity, purity, potency, and consistency.

[§ VI.C in 6b] The physicochemical assessment should consider all relevant characteristics (e.g., primary, secondary, tertiary, and quaternary structure, post-translational modifications, and functional activity(ies)). The applicant should address the concept of the desired product (and its variants) as defined in ICH Q6B.

Using methods that involve different physicochemical or biological principles to assess the same attribute, and using complementary analytical techniques in series, may be especially valuable.

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

[§§ V, VI.D in 6b and VII.B in 6c] Functional assays complement physicochemical analyses, are a quality measure of protein function, and are critical tools for evaluating the integrity of higher order structures. Extensive, robust comparative functional studies should be performed. Physicochemical and functional characterization studies should be sufficient to establish relevant quality attributes including those that define identity, purity, potency, and consistency.

[§ VI.D in 6b] If an Reference Product exhibits multiple functional activities, an applicant should perform a set of relevant assays to evaluate the range of activities. Where a single functional activity can be measured by more than one parameter, comparative characterization of each parameter between products should be used.

Potential limitations of some types of functional assays might preclude detection of small but significant differences between the biosimilar and Reference Product. Applicants are encouraged to develop assays that are sensitive to changes in functional activities.

[§ VII.B in 6c] Information about functional assays, including sensitivity, specificity, and extent of validation, can affect the amount and type of additional animal or clinical data that may be needed to establish biosimilarity.

Immunological

[§ VI.E in 6b] When binding or immunochemical properties are part of the activity attributed to the biosimilar, analytical tests should characterize the product in terms of these properties and the properties should be measured in comparative studies.

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.

[§§ V, VI.F in 6b] Product-related impurities, product-related substances, and process-related impurities should be identified, characterized as appropriate, quantified, and compared to those of the Reference Product to the extent feasible and relevant. If comparative physicochemical analysis reveals different impurities or higher levels of impurities than those in the Reference Product, additional pharmacological/toxicological studies may be necessary.

It is preferable to remove rather than qualify impurities. The potential impact of differences in the biosimilar’s impurity profile on safety should be addressed and supported by appropriate data.

[§ VI.A in 6b] The type of expression system and host cell used will significantly affect the types of process- and product-related substances and impurities that may be present in the biosimilar.

[§ VI.F in 6b] Applicants should screen critical raw materials and ensure robust virus removal and inactivation is achieved by the manufacturing 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.

[§ VI.I in 6b] An applicant should conduct an appropriate physicochemical and functional comparison of the stability of the biosimilar with that of the Reference Product. Accelerated and stress stability studies, or forced degradation studies, should be used to establish degradation profiles and to compare the biosimilar and Reference Product. The comparative studies should be conducted under multiple stress conditions.

Sufficient “real time, real condition” stability data should support the proposed dating period.

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

[§ V in 6b] Manufacturers should perform in-depth chemical, physical, and bioactivity comparisons with side-by-side analyses of an appropriate number of lots of the biosimilar and Reference Product (and, where available and appropriate, a reference standard). Identification of specific lots of the Reference Product used, expiration dates, and timeframes of use will help justify acceptance criteria for specifications to ensure product consistency. Acceptance criteria should be based on the totality of the analytical data and not simply on the observed range of product attributes of the Reference Product.

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).

[42 U.S.C. § 262(k)(2)(A)(i)(I)(bb)] An application must include data derived from animal studies (including the assessment of toxicity).

[42 U.S.C. § 262(k)(2)(A)(ii)] The Secretary may determine that these data are unnecessary.

[§§ VI.A, VII.C.3 in 6c] An applicant should consider the role of animal data in assessing toxicity and, in some cases, in providing additional support for demonstrating biosimilarity and contributing to the immunogenicity assessment. In some cases measurement of anti-protein antibody responses in animals may provide information relevant to patient safety.

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.

[§§ VII.B, VII.C.1 in 6c] In vitro studies: Pharmacologic activity can be evaluated by in vitro and/or in vivo functional assays. These assays may include, but are not limited to, bioassays, biological assays, binding assays, and enzyme kinetics. If animal toxicity studies are not warranted, additional comparative in vitro testing, using human cells or tissues when appropriate, may be warranted.

[§ VII.C.2 in 6c] In vivo studies: Under certain circumstances, a single-dose study in animals comparing the biosimilar and Reference Product using PK and PD measures may contribute to the evidence that supports a demonstration of biosimilarity.

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).

[42 U.S.C. § 262(k)(2)(A)(i)(I)(bb)] An application must include data derived from animal studies (including the assessment of toxicity).

[42 U.S.C. § 262(k)(2)(A)(ii)] The Secretary may determine that these data are unnecessary.

[§ III in 6b] An assessment of biosimilarity “generally” will include animal studies (including the assessment of toxicity).

[§ VII.C.1 in 6c] Animal toxicity studies are useful when, after extensive structural and functional characterization, uncertainties remain about the safety of the biosimilar that need to be addressed before initiation of human clinical studies. The scope and extent of any animal toxicity studies will depend on the information available on the Reference Product, the biosimilar, and the extent of known similarities or differences between the two products. If animal toxicity studies are not warranted, additional comparative in vitro testing may be warranted.

When animal toxicity studies are conducted, it will generally be useful to perform a comparative toxicology study, although an applicant may be able to provide a scientific justification for a stand-alone study.

In general, nonclinical safety pharmacology, reproductive and developmental toxicity, and carcinogenicity studies are not warranted when the biosimilar and Reference Product have been demonstrated to be highly similar through structural and functional characterization and animal toxicity studies (unless there are specific safety concerns based on clinical use of the Reference Product).

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.

[42 U.S.C. § 262(k)(2)(A)(i)(I)(cc)] An application must include data derived from a clinical study or studies, including PK or PD data.

[42 U.S.C. § 262(k)(2)(A)(ii)] The Secretary may determine that these data are unnecessary.

[§ VII.D.1 in 6c] Comparative human PK and (where there is a relevant PD measure) PD studies “generally” will be expected, unless an applicant can justify that an element is unnecessary.

Applicants should justify the human PK and PD study population and parameters. To the extent possible, the applicant should select PD measures that: (1) are relevant to clinical outcomes; (2) can be addressed after a sufficient period of time after dosing, with appropriate precision; and (3) have the sensitivity to detect clinically meaningful differences between the biosimilar and Reference Product.

Establishing a similar human PK and PD profile may provide a basis for a selective and targeted approach to subsequent clinical testing, depending on factors such as whether the studies have used: (1) clinically relevant PK and PD parameters; (2) “populations, dose(s), and route of administration” that are the most sensitive to detect differences in PK and PD profiles; and (3) sensitive and relevant assays. In certain circumstances, human PK and PD data may provide sufficient clinical data to support a demonstration of biosimilarity.

[§ VII.D.4 in 6c] A cross-over design (for products with a short half-life) and parallel study (for products with a longer half-life) is recommended. It is important to select doses for study on the steepest part of the dose-response curve for the biosimilar, whenever possible.

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.

[42 U.S.C. § 262(k)(2)(A)(i)(I)(cc)] An application must include data derived from a clinical study or studies that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the Reference Product is licensed and intended to be used and for which licensure is sought.

[42 U.S.C. § 262(k)(2)(A)(ii)] The Secretary may determine that these data are unnecessary.

[§ VII.D.3 in 6c] Examples of factors that may influence the type and extent of comparative clinical safety and effectiveness data needed, if residual uncertainties persist (after structural and functional characterization, animal testing, human PK and PD testing, and clinical immunogenicity testing), include: (1) the nature and complexity of the Reference Product and the extensiveness and results of structural and functional characterization; (2) the extent to which differences in structure, function, and nonclinical pharmacology and toxicology predict differences in clinical outcomes, as well as the degree of understanding of the MoA of the Reference Product and disease pathology; (3) the extent to which human PK or PD predicts clinical outcomes; (4) the extent of clinical experience with the Reference Product and its therapeutic class; and (5) the extent of any clinical experience with the biosimilar.

Safety or effectiveness concerns regarding the Reference Product and its class (or a lack thereof) may warrant more (or less) comparative clinical safety and effectiveness data.

[§ VII.D.4 in 6c] Clinical studies should be designed to demonstrate the biosimilar has neither decreased nor increased activity compared to the Reference Product. A two-sided study (with an appropriate equivalence margin) is the most straightforward study design, although in some cases a one-sided (non-inferiority design) may be appropriate.

Applicants should use endpoints and study populations that will be clinically relevant and sensitive in detecting clinically meaningful differences. An applicant can use endpoints that are different from those in the Reference Product’s clinical trials if justified. For example, certain PD measures are more sensitive than clinical endpoints and may enable more precise comparisons. The study population should be similar to the population studied for licensure of the Reference Product.

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.

Same as immediately above.

[§ VII.D.4 in 6c] A one-sided test may be adequate in a clinical study evaluating immunogenicity or other safety endpoints as long as it is clear that lower immunogenic or other adverse events would not have effectiveness implications.

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.

[42 U.S.C. § 262(k)(2)(A)(i)(I)(cc)] An application must include data derived from a clinical study or studies (including the assessment of immunogenicity) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the Reference Product is licensed and intended to be used and for which licensure is sought.

[42 U.S.C. § 262(k)(2)(A)(ii)] The Secretary may determine that these data are unnecessary.

[§ VII.D.2 in 6c] At least one clinical study that includes a comparison of the immunogenicity of the biosimilar and the immunogenicity of the Reference Product is generally expected. The extent and timing (e.g., premarket versus postmarket) of a clinical immunogenicity program will vary. If immune response to the Reference Product is rare, a premarket study powered to detect major differences in immune responses and a postmarket study designed to detect more subtle differences may be sufficient.

The design of clinical immunogenicity studies should consider both the incidence and severity of human immune responses. A comparative parallel design is recommended and the study population should be justified. It is generally only important to demonstrate that the immunogenicity of the biosimilar is not increased, so a one-sided design will ordinarily be adequate.

Differences in immune response in the absence of observed clinical sequelae may warrant further evaluation to assess whether there are clinically meaningful differences between the biosimilar and Reference Product. The selection of endpoints or PD measures should take into consideration immunogenicity issues associated with the Reference Product. The biosimilar and Reference Product should be assessed in the same assay with the same patient sera whenever possible.

The follow-up period should be determined based on several factors. The minimal follow-up period for chronically administered agents should be one year, unless a shorter duration is justified.

If an applicant seeks to extrapolate immunogenicity data for one indication to others, it should consider using the study population and treatment regimen that are most sensitive for detecting differences in immune responses.

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.

[§§ VII.D.5 in 6c and A.I.11 in 6d] Extrapolation to other approved indications of the Reference Product may be possible if the applicant provides sufficient scientific justification to support a determination of biosimilarity for each condition of use for which licensure is sought. The scientific justification should address, for example: (1) the MoA(s) in each condition of use for which licensure is sought; (2) the PK and bio-distribution of the product in different patient populations; (3) differences in expected toxicities in each condition of use and patient population; and (4) any other factor that may affect safety or efficacy in each condition of use and patient population for which licensure is sought.

[§ VII.D.5 in 6c] An applicant should consider conducting the clinical study in the condition of use that is the most sensitive in detecting clinically meaningful differences. An applicant should be cautious with respect to extrapolating safety profiles across indications because patient populations for different indications may have different co-morbidities and receive different concomitant medications.

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).

[42 U.S.C. § 262(k)(5)(C)] The Secretary’s “risk evaluation and mitigation strategy” (REMS) authority applies to biosimilars in the same manner as it applies to biological products licensed under section 351(a) the Public Health Service Act.

[§ VIII in 6c] Robust postmarketing safety monitoring is important for biologics. Consideration should be given to safety or effectiveness concerns associated with use of the Reference Product as well as the biosimilar in its development and (if marketed outside the United States) its clinical use.

Adequate mechanisms should be in place to differentiate between averse events associated with the biosimilar and the Reference Product. In particular cases, rare but potentially serious safety risks may need to be evaluated through postmarketing surveillance or studies.

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.

In the US, substitution practices are determined at the state level.

[42 U.S.C. § 262(k)(4)] FDA may find a biosimilar to be interchangeable with the Reference Product if the information submitted by the applicant is sufficient to demonstrate that: (1) the applicant’s product is biosimilar to the Reference Product; and (2) the applicant’s product can be expected to produce the same clinical result as the Reference Product in any given patient.

Additionally, for products administered more than once to an individual, the applicant must demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the biosimilar and use of the Reference Product is not greater than the risk of using the Reference Product without such alternating or switching.

[§§ II, III in 6b and A.I.14 in 6d] Interchangeability is a higher standard than biosimilarity. FDA is continuing to consider the type of information sufficient to enable an interchangeability determination. At this time it would be difficult for an applicant to establish interchangeability in an original biosimilar (section 351(k)) application given the sequential nature of the interchangeability assessment.

[§ A.I.4 in 6d] When making an interchangeability determination, FDA may consider whether a biosimilar’s differences in terms of delivery device or packaging significantly alter critical design attributes, product performance, or operating principles, or would require additional instruction to healthcare providers or patients.

[§ A.I.8 in 6d] At this time it is unlikely that clinical comparisons with a non-U.S.-licensed product would be an adequate basis to support a finding of interchangeability with the Reference Product.

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.

FDA has a separate guidance specific to biosimilar naming
[§ IV] FDA's naming convention for licensed biological products described in this guidance will be a proper name for all biological products within the scope of this guidance that will include a core name and a designated suffix. For interchangeable products, FDA is considering whether the designated suffix should be unique or should be the same as its reference product.
[§ V] The proposed suffix should:
ο Be four lowercase letters
ο Be unique
ο Be devoid of meaning
The proposed suffix should not:
ο Be promotional, such as by making misrepresentations with respect to safety or efficacy
ο Include abbreviations commonly used in clinical practice in a manner that may lead the suffix to be misinterpreted as another element on the prescription or order
ο Contain or suggest any drug substance name or core name designated by the USAN Council
ο Look similar to or be mistaken for the name of a currently marketed product (e.g., should 376 not increase the risk of confusion or medical errors with the product and/or other products in the clinical setting)
ο Be too similar to any other product's suffix designation

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).]

[§ VIII in 6c] A biosimilar’s labeling should include all information necessary for health professionals to make prescribing decisions. It should include a clear statement advising that the product is biosimilar to an Reference Product for a stated indication(s) and route(s) of administration. It should also indicate that the product has (or has not) been determined to be interchangeable with the Reference Product.

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.

[§ V in 6b] A meaningful analytical assessment depends on the capabilities of available state-of-the-art analytical assays to assess, e.g., higher order structure and post-translational modifications, degree of heterogeneity, functional properties, and impurity profiles. The applicant should describe the capability and limitations of the analytical methods used.

Advances in manufacturing science and Quality-by-Design approaches may facilitate production processes that can better match an Reference Product’s “fingerprint.”

[§ VI.C in 6b] For the physicochemical assessment, using methods that involve different physicochemical or biological principles to assess the same attribute, and using complementary analytical techniques in series, may be especially valuable.

[§ VI.B in 6b] The use of Quality-by-Design approaches to pharmaceutical development, along with quality risk management and effective quality systems, will facilitate the consistent manufacturing of a high quality product.

Footnotes

[1] Source: clinicaltrials.gov (active studies including keyword: biosimilar. Accessed March 2016)

CBPE

Number of Biosimilars Available

Country Spotlight: USA

Biosimilars Available

Score Overview

USA is Fully Compliant.

Scores by measured component

Gaps

Gap 1

Gap 2

Gap 3

Overall country score as compared to peers

History of Policy

Policy Guidelines

Side by side comparison of each of the score components

Footnotes