Number of Biosimilars Available
2
Country Spotlight: Brazil
The Brazilian Health Surveillance Agency ANVISA (Agência Nacional de Vigilância Sanitária) is responsible is responsible for the regulation and approval of pharmaceutical drugs, including the scientific evaluation of biologics and biosimilars. ANVISA comes under the authority of the Ministry of Health–Mínistério de Saúde.
In Brazil, biosimilars are known as follow on biological products.
Biosimilars Available
As of April 2016, there are 2 biosimilars approved for use in Brazil
- A medicine 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)
- A medicine used to treat Rheumatoid Arthritis, Psoriatic Arthritis, Psoriasis, and Ankylosing Spondylitis, Ulcerative colitis and Crohn’s disease (infliximab)
Score Overview
Brazil is Partially Compliant.
The WHO guidance was compared to the relevant sections across the ANVISA guidelines resulting in an overall score for Brazil of 3.28/5. This means the ANVISA guidelines are partially or fully compliant with the WHO in some areas, exceed the WHO standards in some areas, and are minimally or non-compliant with the WHO standards in some areas.
The graph below shows individual scores by each of the 28 components of biosimilar policy
There are ten areas where ANVISA is not as specific as WHO, being either non-compliant, minimally compliant, or partially compliant with the WHO biosimilar policy.
Scores by measured component
Gaps
Gap 1
Reference Product:
When comparing the biosimilar to the original medicine, the ANVISA guidelines do not specify that the same host cell should be used to produce the medicine.
Gap 2
Route of Administration:
The guidelines are vague as to whether the route of administration for the biosimilar should be the same as for the original biologic.
Gap 3
Quality/analytical, General Considerations:
The guidelines do not address that an investigation into differences between the biosimilar and the original biologic should take into account lot-to-lot differences in commercial lots of the original biologic.
Gap 4
Nonclinical, Pharmacology (in vivo and in vitro):
The guidelines do not address the need for in vitro studies.
Gap 5
Nonclinical, Pharmacokinetics:
This topic is not addressed by the ANVISA guidelines.
Gap 6
Clinical, Immunogenicity:
The guidelines do provide an adequate level of detail on how to evaluate clinical immunogenicity
Gap 7
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 8
Interchangeability:
This topic is not addressed by the ANVISA guidelines.
Gap 9
Naming:
This topic is not addressed by the ANVISA guidelines.
Gap 10
Labeling:
This topic is not addressed by the ANVISA guidelines.
Overall country score as compared to peers
History of Policy
Brazil developed their biosimilar regulations in 2010 (Resolution no. 55/2010).[1] The guidelines follow the principles of the WHO biosimilars guidance.
Policy Guidelines
- This guideline provides two regulatory pathways for biosimilars: a comparative pathway and an individual development pathway. In the individual development pathway, a reduced dossier can be presented. The applicant needs to present complete data regarding quality issues but it does not have to be comparative
- First issued December 2010; Most recent update December 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).
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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.
[Arts. 2, 4 in 3a] Includes: (1) vaccines; (2) hyper-immune serums (whole or fragmented heterologous, purified immunoglobulins, obtained from the plasma of hyper-immunized animals with toxic substances from animals, microorganisms, or viruses); (3) hemoderivatives (products obtained from human plasma); (4) biodrugs (drugs obtained from biological fluids or tissues of animal origin and drugs obtained through biotechnology); (5) monoclonal antibodies; and (6) drugs containing live, attenuated, or dead microorganisms.
[Art. 5 in 3a] Excludes: (1) antibiotics; (2) semi-synthetic conjugated estrogens (anovulatory); (3) probiotics; and (4) allergenic products.
[Arts. 2, 26, 39, 41 in 3a, § 2 in 3b] There are two pathways for the approval of follow-on biological products: (1) the comparability route (for the approval of products — biosimilars — on the basis of a comparability exercise); and (2) the “independent development” route (for the approval of products — that are not similar enough to an Reference Product to qualify as a biosimilar — on the basis of “full data” concerning product development, production, quality control, (potentially reduced) nonclinical data, and comparative clinical data).
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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.
Comparability route
[Art. 2 in 3a] A biosimilar is a biologic that is not new in that it contains a molecule with known biological activity (that has already been registered in Brazil) and that has already undergone all stages of manufacturing.
Comparability is the scientific comparison between a biosimilar and an Reference Product to establish that there are no detectable differences in terms of quality, efficacy, and safety.
[Art. 43 in 3a] All studies must be comparative in nature.
[§1 in 3b] The comparability exercise should start with characterization and evaluation of the product’s quality attributes and be followed by nonclinical and clinical studies.
[§ 2 in 3b] The number of studies required depends on the nature of the product, the availability of analytical techniques that allow the detection of potential differences between the product and the Reference Product, and the relationship between quality attributes and the product’s safety and efficacy profile.
[§ 6 in 3b] Final determination of similarity between the biosimilar and the Reference Product must be based on: (1) analyses; (2) biological assays; and (3) data obtained from clinical and nonclinical studies. The majority of data must concern an analytical and biological characterization.
Individual development route
[Art. 2 in 3a, § 2 in 3b] If during the comparability exercise significant differences are detected between the product and the Reference Product that cannot be justified, the product must be submitted for registration under the individual development route. More extensive nonclinical and clinical data will be required than are required under the comparability route.
[§ 6 in 3b] The individual development route must be used in the following cases: (1) the analytical techniques used do not allow for identification of pertinent differences that may affect safety and efficacy; or (2) “the link between certain quality attributes, like safety and efficacy, was not established” and it is likely that there are differences between the quality attributes of the product and an Reference Product.
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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.
Comparability route
[Arts. 2, 27 in 3a] The reference product must be a product registered with ANVISA (the National Health Surveillance Agency) on the basis of a complete dossier and must have been sold in Brazil.
If such a product is not commercially available in Brazil or internationally, the applicant should propose, and receive ANVISA’s consent, to use a different product as the reference product. A product that is registered by another regulatory authority that has technical-scientific approval criteria similar to those of ANVISA, and for which there is a possibility for ANVISA to have full and unrestricted access to its registration information, will be a candidate for an reference product.
[Art. 27 in 3a, § 1 in 3b] The same reference product should be used in all stages of the comparability exercise.
Individual development route
[Art. 41 in 3a] Phase III clinical studies must be comparative (non-inferiority, clinical equivalence or superiority) in nature.
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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.
[Art. 31 in 3a] For both routes, the applicant must submit information about the full composition of the formulation. All components must be identified using the technical names and synonyms according to the Brazilian Common Denomination (DCB), if any, or the International Common Denomination (ICD). In the absence of these names, the Chemical Abstracts Service (CAS) denomination should be used. The units of measurement as well as functions performed by each substance in the formulation should be provided.
The applicant must submit the following information related to excipients used: (1) a description of physicochemical and microbiological properties and quality controls; (2) excipients specifications; (3) a description of possible chemical interactions between the excipients and the active ingredient; and (4) results of a study demonstrating efficacy of the preservative, for those products that contain a preservative in the final formulation.
Comparability route
[§ 3 in 3b] Some differences between the biosimilar and the Reference Product are likely, for example due to differences in excipients.
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Route of Administration
[§ 5.0 ] Same as that of the RP.
[Art. 31 in 3a] For both routes, the applicant must submit information about the route(s) of administration.
Comparability route
[§ 1 in 3b] Same as that of the Reference Product.
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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.
[Art. 31 in 3a] For both routes, the applicant must submit information about the dosage form and presentation.
Comparability route
[§ 1 in 3b] Dosage form must be the same as that of the Reference Product.
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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.
Comparability route
[Art. 46 in 3a] The applicant must submit protocols for, and reports with the results of, the following clinical studies: (1) PK studies; (2) PD studies; and (3) pivotal clinical safety and efficacy studies.
The comparative clinical studies must demonstrate comparability of the efficacy and safety profiles between the biosimilar and the Reference Product.
[§ 1 in 3b] The quantity of clinical (and nonclinical) data deemed necessary will depend on: (1) the product or class of products; (2) the level of characterization with modern analytical methods; (3) differences observed or potential differences between the biosimilar and the Reference Product; and (4) the clinical experience with the product class. A case-by-case analysis is clearly required for each product class.
The “main clinical studies” should use product manufactured with the biosimilar’s final manufacturing process. If product manufactured with a non-final process is used, additional evidence may be required to demonstrate comparability of the biosimilar studied clinically and the biosimilar to be marketed.
Individual development route
[Art. 40 in 3a] Phase I and II clinical studies, when necessary, will not (necessarily) be comparative.
[Art. 41 in 3a] Phase III clinical studies will always be necessary, and they must be comparative (non-inferiority, clinical equivalence or superiority), except when the product is a hemoderivative, vaccine, or biologic with an oncological indication.
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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.
Comparability route
[Art. 43 in 3a] If there is need to isolate the active substance of the Reference Product, the applicant must submit studies demonstrating that the active ingredient was not altered by the isolation process.
[§ 3 in 3b] One method for qualifying the isolation process is addressed. The methods used to qualify the isolation process must be justified.
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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.
[Art. 34 in 3a] For both routes, the application must identify the physicochemical properties at the active substance and finished product levels.
Comparability route
[Art. 43 in 3a] The application must contain data on the biological and physicochemical characterization of the biosimilar.
[§ 3 in 3b] The applicant must perform a full physicochemical and biological characterization directly comparing the biosimilar and the Reference Product. All quality aspects must be evaluated.
[§ 3.1.1 in 3b] More than one analysis technique may be required to evaluate the same quality attribute.
Details must be provided on the primary and higher order structure and post-translational modifications (including but not limited to glycoforms).
[§ 3.1.2 in 3b] The primary structure of the biosimilar and the Reference Product must be identical.
[§ 3.1.3 in 3b] Post-translationally modified forms and their potential differences must be investigated, identified, and characterized, and their effects must be analyzed.
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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
[Art. 34 in 3a] For both routes, the application must describe the biological activity at the active substance and finished product levels.
Comparability route — biological
[Art. 43 in 3a] The application must contain results of comparative biological tests required to determine the level of comparability between the biosimilar and the Reference Product.
[§ 3.1.1 in 3b] Details must be provided on the biological activity of the biosimilar and the Reference Product.
[§ 3.1.4 in 3b] Ideally, the biological evaluation will serve as a link to clinical activity. It can also be used to determine if a variant of a product has a suitable level of activity (and is a substance related to the product) or is inactive (and is an impurity).
Potency is the quantitative measure of the biological activity. A relevant and validated potency test must be part of the comparability exercise.
Immunological
[Art. 34 in 3a] For both routes, the application must describe immunological properties at the active substance and finished product levels.
Comparability route — immunological
[§ 3.1.1 in 3b] Details must be provided on the immunochemical properties of the biosimilar and the Reference Product, when pertinent.
[§ 3.1.4 in 3b] A relevant biological test is essential to determine if the antibodies developed have neutralizing activity that affects the biological activity of the biosimilar and/or endogenous counterparts, if present.
[§ 3.15 in 3b] When the characterization includes immunochemical properties (e.g., in the cases of antibodies or antibody-based products), the manufacturer must confirm that the biosimilar is equivalent to the Reference Product in terms of specificity, affinity, bond kinetics, and Fc functional activity, when pertinent.
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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.
[Art. 31 in 3a] For both routes, the applicant must submit the following information: (1) characterization of contaminants and impurities; (2) a description of the processes involved in reducing/removing product-related and process-related impurities; (3) justifications for the impurities specifications for the finished product; and (4) a safety evaluation for adventitious agents introduced by starting materials.
[Art. 34 in 3a] The application must describe the level of purity and aggregates at the active substance and finished product levels.
Comparability route
[Art. 43 in 3a] The application must contain a report describing the differences observed in the purity and impurity profiles of the biosimilar and the Reference Product.
An application must contain an evaluation of the contaminants and impurities identified in the biosimilar and discuss the potential effect on quality, safety, and efficacy.
[§ 3.1.6 in 3a] Impurities related to the process and product must be identified, quantified with state-of-the-art technology, and compared with those of the Reference Product. Some differences will be expected because the proteins are produced by different manufacturing processes. If significant differences are observed , the potential effect of those differences on the efficacy and safety of the biosimilar, including the potential effect on immunogenicity, must be evaluated and discussed.
It is essential to conduct tests to verify the process-related impurities that are specific to the cell line used.
[§ 5 in 3b] As a general rule, the biosimilar must be expressed and produced in the same type of host cell as the Reference Product to minimize the potential for important differences in critical quality attributes and to prevent the introduction of certain types of process-related impurities.
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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.
[Art. 31 in 3a] For both routes, the applicant must submit a protocol for stability studies and report the results of those studies.
Comparability route
[Art. 43 in 3a] An application must contain reports of comparative stability studies conducted under accelerated and stress conditions.
[§ 2 in 3b] The applicant must evaluate data on stability to better understand potential differences related to product breakdown routes and impurities.
[§ 4 in 3b] In exceptional cases, it may be useful or necessary to conduct comparative stability tests in real time/under real storage conditions to compare the stability of both products.
Stability studies must be conducted according to Resolution RDC No. 50/11 and its updates such as RDC No. 50/13.
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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
[Art. 31 in 3a] For both routes, the application must justify each quality control specification.
Comparability route
[§ 3.1.7 in 3b] The specification tests and analyses for the drug substance or the finished product are not suitable to evaluate the differences between the biosimilar and the Reference Product, since they serve routine quality control purposes and do not provide a complete characterization.
The applicant must confirm that the biosimilar’s specifications can assure product quality. Specifications must be established as described in guidelines and monographs, when these exist. Pharmacopoeial monographs may contain only a minimum set of requirements, however, and additional test parameters may be required. The analytical methods must be validated and the analytical methods and acceptance limits must be justified.
[§ 3.1.7 in 3b] The biosimilar’s specifications may not be the same as those for the Reference Product, since the two products’ manufacturing processes and analytical and laboratory procedures used will be different. The biosimilar’s specifications must control for known important quality attributes. The applicant must demonstrate, whenever possible, that the limits established for a given specification are not significantly greater than the range of variability of the Reference Product during the maximum storage period of the product, unless otherwise justified.
[§ 3.1.4 in 3b] A relevant and validated potency test must be part of the active ingredient and/or finished product specification.
Individual development route
[Art. 38 in 3a] Production and quality control data must meet the quality standards already established “for the product to be registered.”
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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).
Comparability route
[Art. 44 in 3a] Nonclinical studies must be comparative in nature and designed to detect significant differences between the biosimilar and the Reference Product.
[§ 1 in 3b] The quantity of nonclinical (and clinical) data deemed necessary will depend on: (1) the product or class of products; (2) the level of characterization with modern analytical methods; (3) differences observed or potential differences between the biosimilar and the Reference Product; and (4) the clinical experience with the product class. A case-by-case analysis is clearly required for each product class.
Individual development route
[Art. 39 in 3a] The extent of nonclinical data needed may be reduced, taking into consideration factors like molecule complexity, level of structure characterization, extent of characterization of the impurity profile, the MoA, the toxicity potential, and the “therapeutic index.”
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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.
Comparability route
[Art. 45 in 3a] In vivo studies: The applicant must submit reports of: (1) relevant PD studies for the intended therapeutic indications; and (2) cumulative toxicity studies (repeated dose), including characterization of TK parameters, conducted in relevant species.
Individual development route
Not addressed.
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Pharmacokinetics
[§ 9.2] Nonclinical evaluation normally encompasses a broad spectrum of studies, including PK studies. The amount of data is highly dependent on the product and class-related factors.
Not addressed.
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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).Comparability route
[Art. 45 in 3a] The applicant must submit cumulative toxicity studies (repeated dose), including characterization of TK parameters, conducted in relevant species.
Individual development route
Not addressed.
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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.Comparability route
[Art. 46 in 3a] The applicant must submit protocols for, and reports with the results of, PK and PD studies. The PD studies may be combined with PK studies, provided that the PK/PD relation is characterized.
Independent development route
Not addressed.
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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.
Comparability route
[Art. 46 in 3a] The applicant must submit protocols for, and reports with the results of, pivotal clinical safety and efficacy studies. The comparative clinical studies must demonstrate comparability of the biosimilar’s and Reference Product’s efficacy and safety profiles.
The design and comparability margins of pivotal clinical safety and efficacy studies must be specified and statistically and clinically supported.
Phase IV study results must be submitted when available.
Individual development route
[Art. 40 in 3a] Phase I and II clinical studies, when necessary, need not (necessarily) be comparative.
[Art. 41 in 3a] Phase III clinical studies will always be necessary, and they must be comparative (non-inferiority, clinical equivalence or superiority), except when the product is a hemoderivative, vaccine, or biologic with an oncological indication.
[Art. 42 in 3a] When available, phase IV clinical studies results must be submitted.
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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.
Comparability route
[Art. 46 in 3a] The applicant must submit protocols for, and reports with the results of, pivotal clinical safety and efficacy studies. The comparative clinical studies must demonstrate comparability of the biosimilar’s and the Reference Product’s efficacy and safety profiles.
The design and comparability margins of pivotal clinical safety and efficacy studies must be specified and statistically and clinically supported.
Individual development route
[Art. 40 in 3a] Phase I and II clinical studies, when necessary, need not (necessarily) be comparative.
[Art. 41 in 3a] Phase III clinical studies will always be necessary, and they must be comparative (non-inferiority, clinical equivalence or superiority),except when the product is a hemoderivative, vaccine, or biologic with an oncological indication.
[Art. 42 in 3a] When available, phase IV clinical studies results must be submitted.
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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.
[Art. 28 in 3a] For both routes, the applicant must submit an immunogenicity study report.
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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.
[Art. 18 in 3a] For both routes, all requested indications must be documented in clinical study reports .
Comparability route
[Art. 19 in 3a] Extrapolation will be addressed in “specific guides.”
To permit extrapolation, the biosimilar and the Reference Product must have comparable safety and efficacy in a clinical model able to detect potential differences between the products, the safety and immunogenicity of the biosimilar must be sufficiently characterized, and the MoA and receptors involved must be the same.
Individual development route
[Art. 20 in 3a] Extrapolation of safety and efficacy data is not possible.
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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).
[Art. 29 in 3a] The applicant must present a PV plan and a risk minimization plan in accordance with (other) legal requirements.
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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.
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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.
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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.
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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.
[Art. 17 in 3a] For both routes, good manufacturing practices should be followed.
Comparability route
[§ 3.1.1 in 3b] A series of modern analyses are required to determine the structure, function, purity and heterogeneity of a biosimilar. The aim of the comparability investigation is to be as complete as possible, to minimize the possibility of undetected differences between the Reference Product and the biosimilar that could affect clinical activity.
[§ 5 in 3b] A biosimilar’s manufacturing process must use state-of-the-art science and technology to obtain a high quality product that is as similar as possible to the Reference Product. A broad evaluation of the Reference Product should be conducted before developing the biosimilar’s manufacturing process. The applicant must consider all available knowledge on the Reference Product with regard to its host cell, formulation, and container closure system. Where applicable, the applicant must determine the potential effect of alteration of any of these elements on quality, safety, and efficacy of the product, based on evidence available from public information and experience with use of the Reference Product.