CBPE

Promoting science based, medically appropriate policies for biologic medicines

Number of Biosimilars Available

Not publicly available

Country Spotlight: Argentina

In Argentina, the regulatory body for approval of medicines, including the scientific evaluation of biologics and biosimilars is the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (National Administration of Drugs, Foods and Medical Devices; ANMAT). ANMAT comes under the authority of the Ministry of Health.

In Argentina, biosimilars are known as Medicamento biológico similar (similar biological medicines)

Biosimilars Available

Not publicly available.

Score Overview

Argentina is Partially Compliant.

The WHO guidance was compared to the relevant sections across the ANMAT guidelines resulting in an overall score for Argentina of 2.57/5. This means the ANMAT guidelines are partially or fully compliant with WHO in some areas, but in more than half of the policy components, they are minimally or non-compliant with WHO standards.

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

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

Gaps

Gap 1

Reference Product:

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

Gap 2

Quality/analytical, General Considerations:

The guidelines do not address that an investigation of differences between the biosimilar and the original biologic should take into account lot-to-lot differences in commercial lots of the original biologic.

Gap 3

Quality/analytical, Biological Analysis:

The guidelines do not specify the intent of this analysis is to identify significant functional differences between the biologic and biosimilar.

Gap 4

Quality/analytical, Immunological Analysis:

The guidelines do not specify the intent of this analysis is to identify significant functional differences between the biologic and biosimilar.

Gap 5

Quality/Analytical, Stability Studies:

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

Gap 6

Nonclinical, Pharmacology (in vivo and in vitro):

The guidelines do not address in vitro studies and in vivo study description does not provide the level of specificity and detail provided by the WHO.

Gap 7

Nonclinical, Pharmacokinetics:

This topic is not addressed by the ANMAT guidelines.

Gap 8

Nonclinical, Toxicology:

This topic is not addressed by the ANMAT guidelines.

Gap 9

Clinical, General Considerations:

The guidelines do not specify that the comparison of a biosimilar with the original biologic should begin with pharmacokinetic and pharmacodynamics studies.

Gap 10

Clinical, Pharmacokinetics and Pharmacodynamics:

This topic is not addressed by the ANMAT guidelines.

Gap 11

Clinical, Immunogenicity:

This topic is not addressed by the ANMAT guidelines.

Gap 12

Indication Extrapolation:

The guidelines 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 original biologic, regardless of whether those indications have been studied.

Gap 13

Interchangeability:

This topic is not addressed by the ANMAT guidelines.

Gap 14

Naming:

This topic is not addressed by the ANMAT guidelines.

Gap 15

Labeling:

This topic is not addressed by the ANMAT guidelines.

Overall country score as compared to peers

History of Policy

In Argentina, biosimilar guidelines were issued in 2008 by ANMAT.[1] The guidelines follow the principles of the EU biosimilars guidance.

Policy Guidelines

Guideline on Biological Medicinal Products

This guideline 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 July 2008; Most recent update July 2008

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.

[§ 3 in 2a] Biological products containing well-characterized proteins.

[§ 4 in 2a] Excludes products using clearly different manufacturing processes from that of the Reference Product (e.g., use of transgenic organisms vs. cell cultures).

[Annex 1, ch. III in 2b] Excludes: (1) vaccines regulated by Regulation 705/05; (2) products not requiring registration in the Registry of Medicinal Products; (3) individualized allergenic vaccines; and (4) human whole blood, plasma, and blood cells, and their components.

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.

[§ 3 in 2a] The comparability exercise must be designed to demonstrate that the biosimilar has quality attributes highly similar to those of the reference product.

[§ 4 in 2a] Through characterization and analysis, the biosimilar must be shown to have similar behavior to the Reference Product in terms of quality, safety, and efficacy.

[§ 8 in 2a] If significant differences are observed between the proposed product and the Reference Product after evaluating the quality, nonclinical, and clinical data, licensing of the proposed product (as a biosimilar) may be denied.

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.

[§ 2 in 2a] Comparisons between the biosimilar and the reference product should always use the same reference product.

[§ 4 in 2a] The reference product must: (1) be licensed by the regulatory authority (ANMAT) and marketed in Argentina; or (2) be licensed by another health authority with regulatory functions, principles, and PV activities in line with those of Argentina, have sufficient experience and knowledge regarding its use in the market available, and have information on its specifications and characteristics available.

The reference product must be licensed based on the evaluation of a full dossier, including quality, nonclinical, and clinical information.

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.

[Annex I, ch. III in 2b] Information related to product formulation and its components must be available for verification. Qualitative and quantitative composition, as well as the function of each substance in the formulation, must be specified.

Specifications and limits for excipients must be provided if they are not in official pharmacopoeias. A full description of the analytical method must be submitted for excipients that are not in official pharmacopoeias and are used for the first time in a medicinal 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 in 2a] Dosage form and “concentration” must 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.

[§ 2 in 2a] The applicant must submit data from trials demonstrating “similar behavior” between the biosimilar and reference product in terms of identity, potency, purity, safety, and efficacy. Comparisons between the biosimilar and the Reference Product should be head-to-head comparisons.

[§ 6 in 2a] The comparability exercise must be accompanied by clinical (and nonclinical) studies. The requirements for these studies will be determined by: (1) the nature of the active substance and its structural complexity; (2) information on the in vivo behavior of the active pharmaceutical ingredient and/or product; (3) impurities; (4) information on the post-market behavior of “similar products”; and (5) the relationship between adverse reactions and molecular characteristics.

[§ 8 in 2a] The ANMAT may require additional clinical data if significant differences are observed during the comparability exercise.

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 in 2a] If the reference product’s active ingredient is obtained through isolation, the applicant must submit studies demonstrating that the active ingredient has not suffered changes during the isolation process. The applicant must use a battery of state-of-the-art tests to determine the structure, function, purity, and heterogeneity of the active ingredient.

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.

[§ 3 in 2a] Adequate physicochemical and biological trials must enable the detailed characterization of the biosimilar.

[§ 5 in 2a] The applicant must use appropriate techniques to determine the biosimilar’s physicochemical products.

The comparability exercise should take into account the complexity of the molecular entity. Depending on the molecule’s physicochemical properties (e.g., primary, secondary, tertiary, and quaternary structure, with or without post-translational modifications, or degree of glycosylation and N/C terminal modifications), an extended battery of tests may be required.

[§ 6 in 2a] The nature of the active substance and its structural complexity are factors in determining the requirements for clinical and nonclinical studies.

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.

[§ 5 in 2a] The applicant must use appropriate techniques to determine “biological and immunochemical” activity (if applicable).

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 in 2a] The applicant must use appropriate techniques to identify impurities.

[§ 6 in 2a] The comparison of the reference product’s and biosimilar’s impurity profiles is a factor in determining the requirements for clinical and nonclinical studies.

[Annex I, ch. III in 2b] An applicant must submit information about starting materials, including quality specifications and the detection of adventitious agents. When using animal and/or human origin components, the applicant must submit evidence of the absence of foreign agents or of the ability to eliminate or reduce these agents during the manufacturing process.

Testing results must be submitted for a minimum of three batches.

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

[Annex I, ch. III in 2b] For the finished product, if the quality specification is from the Argentine Pharmacopoeia or another internationally recognized pharmacopoeia, the application must indicate the specifications and limits applied, along with the acceptance/rejection criteria.

If the specification is determined by the manufacturer, the applicant must submit: (1) information about the physicochemical, biochemical, and immunological characterization of the biosimilar; (2) information about the biosimilar’s purity and impurity profiles; (3) a full description of analytical methods used, their limits, and acceptance/rejection criteria; and (4) reference standards or materials used and information about their validation.

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).

[§ 6 in 2a] The comparability exercise must be accompanied by nonclinical (and clinical) studies. The requirements for these studies will be determined by: (1) the nature of the active substance and its structural complexity; (2) information on the in vivo behavior of the active pharmaceutical ingredient and/or product, (3) impurities; (4) information on the post-market behavior of “similar products”; and (5) the relationship between adverse reactions and molecular characteristics.

[§ 8 in 2a] The ANMAT may require additional nonclinical data if significant differences are observed during the comparability exercise.

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.

[§6 in 2a] In vivo studies: Requirements for nonclinical (and clinical) studies will be determined by, among other factors, information on the in vivo behavior of the active ingredient and/or 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.

Not addressed.

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.

[§ 2 in 2a] The applicant must submit evidence demonstrating “similar behavior” in terms of safety and efficacy. Comparisons between the biosimilar and the Reference Product should be head-to-head comparisons.

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.

[§ 2 in 2a] The applicant must submit evidence demonstrating “similar behavior” in terms of safety and efficacy. Comparisons between the biosimilar and the Reference Product should be head-to-head comparisons.

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.

[§ 4 in 2a] The indications of the biosimilar must be the same as those for which the Reference Product was approved. Scientific data supporting each indication must be available.

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 2a] The applicant must assure that by the time of licensing there will be in place an appropriate post-market surveillance system. It should include a qualified professional in charge of supervising the system and adequate provisions for providing notice of adverse reactions occurring in Argentina and abroad.

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.

Not addressed.

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.

Not addressed.

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.

[§ 4 in 2a] A biosimilar is well-characterized through the use of an established battery of modern analytical methods.

[§ 4 in 2a] The applicant must use a battery of state-of-the-art tests to determine structure, function, purity, and heterogeneity of the active ingredient.

Footnotes

[1] Source: http://gabionline.net/Biosimilars/Research/Regulation-of-similar-biotherapeutic-products-in-Latin-America