CBPE

Promoting science based, medically appropriate policies for biologic medicines

South Africa
Number of Biosimilars Available

Not publicly available

Country Spotlight: South Africa

In South Africa, the Medicines Control Council (MCC) is the statutory body that regulates the performance of clinical trials and registration of medicines and medical devices for use in specific diseases. Within the MCC, the Biological Medicines Committee evaluates biological agents, including biosimilars.

Biosimilars Available

Not publicly available.

Score Overview

South Africa is Partially Compliant.

The WHO guidance was compared to the relevant sections across the MCC guidelines resulting in an overall score for South Africa is 2.35/5. This means the MCC guidelines are partially or fully compliant with WHO in some areas, but in at least 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 fourteen areas where MCC 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:

The MCC does not provide as much detail as the WHO, instead simply stating that the reference product should be registered in South Africa

Gap 2

Formulation:

The MCC does not provide as much detail as the WHO, instead simply stating that the reference product should be registered in South Africa

Gap 3

Route of Administration:

This topic is not addressed in the MCC guidelines

Gap 4

Dosage Form and Strength:

This topic is not addressed in the MCC guidelines

Gap 5

Quality/Analytical, Biological Analysis:

The guidelines do not provide appropriate detail as to the analytical biological tests that should be used to demonstrate biosimilarity. First, that those chosen should reflect the mechanism of action of the biologic; and second that they should be precise and accurate enough to identify any functional differences between the biosimilar and the biologic.

Gap 6

Quality/Analytical, Immunological Analysis:

The guidelines indicate that the purpose of immunological studies is to identify the potential for adverse reactions only, while the expectation of the WHO guideline is that data from these studies should provide a more expansive characterization.

Gap 7

Quality/Analytical, Impurities:

This topic is not addressed in the MCC guidelines

Gap 8

Quality/Analytical, Stability Studies:

This topic is not addressed in the MCC guidelines

Gap 9

Quality/Analytical, Specifications:

This topic is not addressed in the MCC guidelines

Gap 10

Nonclinical, Pharmacokinetics:

This topic is not addressed by the MCC guidelines.

Gap 11

Clinical, General Considerations:

The guidelines do not address the fact that if relevant differences between the biologic and biosimilar are identified, the new product may not qualify as a biosimilar and a full licensing application should be considered.

Gap 12

Indication Extrapolation:

This topic is not addressed by the MCC guidelines.

Gap 13

Naming:

This topic is not addressed by the MCC guidelines.

Gap 14

Labeling:

This topic is not addressed by the MCC guidelines.

Gap 15

Manufacturing and Analytical Technology:

The guidelines do not mention the product and manufacturing controls that are needed to ensure the manufacture of a high quality biosimilar

Overall country score as compared to peers

History of Policy

South Africa first published their guidelines, Biosimilar medicines: quality, non-clinical and clinical requirements in March 2012. This guideline was amended in August 2014 to include requirements for filing for regulatory approval for monoclonal antibody biosimilars. The guidelines follow the principles of both the EU and WHO biosimilars guidelines.

Policy Guidelines

Biosimilar medicines: quality, non-clinical and clinical requirements

  • 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 March 2012; Most recent update August 2014

Side by side comparison of each of the score components

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

Scope

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

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

[§ 2.0] Well-characterized biological medicines containing recombinant DNA-derived therapeutic proteins.

Excludes vaccines, plasma-derived products, recombinant blood factors, and monoclonal antibodies.

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.

[§ 6.0] A biosimilar is a biological medicine that is similar, but not identical, to an already registered Reference Product in terms of quality, safety, and efficacy.

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.

[§ 5.2, 6] The reference product should be registered in S. Africa.

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.

[§ 5.3] The formulation of a biosimilar may be different from that of its reference product.

Route of Administration

[§ 5.0 ] Same as that of the RP.

Not addressed.

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.

Not addressed.

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.

[§ 5.2] Clinical studies should have the following characteristics: (1) the final product (formulation) should be compared to an Reference Product; (2) the Reference Product should be registered in S. Africa; (3) the non-inferior safety of the biosimilar must be established; (4) the equivalent efficacy of the final product (formulation) must be established; (5) there must be evidence for efficacy and safety for each indication; and (6) a risk benefit analysis of the biosimilar must be performed.

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.

[§ 5.1.1] If the active substance in the Reference Product needs to be purified from a formulated Reference Product in order to be suitable for characterization, studies must be carried out to demonstrate that product heterogeneity and relevant attributes of the active moiety are not affected by the isolation process.

The approach employed to isolate and compare the biosimilar active substance to the reference active substance should be justified (with data) as appropriate for the intended purpose. Where possible, the product should be tested with and without manipulation.

Physicochemical Analysis

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

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

[§ 5.1.2] Primary, secondary, and tertiary structure should be demonstrated, as well as the composition and structure of post-translational modifications. These studies should, where possible, be conducted in comparison with the Reference Product.

Biological and Immunological Analysis

Biological

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

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

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

Immunological

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

Biological

[§ 5.1.2] Biological assays like receptor-binding assays or cell-based assays should be used to establish comparability.

Immunological

[§ 5.1.2] Molecular characterization should include analysis and comparison of antigenic epitopes that could lead to adverse reactions.

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.

Not addressed.

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.

Not addressed.

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

Not addressed.

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).

[§ 5.1] Nonclinical studies should be: (1) performed before initiating clinical development; (2) comparative in nature; and (3) designed to detect differences in response between the biosimilar and the Reference Product, and not just the response per se.

The objective is to establish the chemical and molecular nature of the active ingredient and to show that it has no detectable differences in physicochemical characteristics when compared to the active ingredient in the Reference Product.

Analytical techniques that can show the comparable functionality of the biosimilar and the Reference Product in appropriate in vivo and in vitro systems should be used. In vivo animal studies to show comparable toxicology and activity should be presented.

Pharmacology

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

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

[§ 5.1.2] In vitro studies: Molecular characterization should be as extensive as possible within the limits of technology (these studies should be conducted in comparison to the Reference Product). Assays like receptor-binding and cell-based assays, which may be available from the quality-related bioassays, should normally be undertaken to establish comparability in reactivity and likely causative factors if comparability cannot be established.

[§ 5.1.3] In vivo studies: PD effect/activity relevant to clinical application should be evaluated. (These data should be available from biological assays in the quality part of the dossier.)

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.

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).

[§5.1.3] Toxicity should be evaluated in at least one repeat-dose study (including TK measurements). TK measurements should include determination of antibody titres, cross reactivity, and neutralizing capacity. Duration of the studies should be long enough to allow detection of relevant differences in toxicity and/or immune responses between the biosimilar and Reference Product. Specific safety concerns could be addressed by including relevant observations in the same repeat-dose toxicity study.

Safety pharmacology, reproduction toxicology, mutagenicity, and carcinogenicity studies are not normally required unless they are indicated in results from repeat-dose toxicity studies.

PK and PD

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

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

[§ 5.2.1] Comparative PK studies designed to demonstrate clinical comparability between the biosimilar and the Reference Product are an essential part of the comparability exercise. Specific considerations related to the inherent characteristics of proteins described in the [European Medicines Agency (EMA) guideline] should be taken into account. Differences in elimination characteristics between products (e.g., clearance and elimination half-life) should be explored.

The choice of the design for single-dose studies, steady-state studies, or repeated determination of PK parameters should be justified.

[§ 5.2.2] PD markers should be selected on the basis of their relevance to demonstrate therapeutic efficacy of the product. The PD effect of the test and the Reference Product should be compared in a population where the possible differences can best be observed. The design and duration of the studies must be justified.

[§ 5.2.3] Normally comparative clinical trials are required for the demonstration of clinical comparability. In certain cases, however, comparative PK/PD studies between the biosimilar and the Reference Product may be sufficient to demonstrate clinical comparability.

Efficacy Assessment

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

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

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

[§ 5.2.3, 5.2.4] Comparative clinical trials will usually be necessary to demonstrate clinical comparability between the biosimilar and the Reference Product. Confirmatory PK/PD may be used in lieu of efficacy trials if: (1) the PK profile of the Reference Product is well-characterized; (2) there is sufficient knowledge of the PD properties of the Reference Product; (3) the relationship between dose/exposure and response/efficacy of the Reference Product is sufficiently characterized; and (4) at least one PD marker is accepted as a surrogate marker for efficacy and the relationship between dose/exposure to the product and this surrogate marker is well known.

[5.2.4] Clinical comparability margins should be pre-specified and justified, primarily on clinical grounds. Assay sensitivity must be ensured.

If a clinical comparability trial design is not feasible, other designs should be explored and their use discussed with the competent authorities.

Safety

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

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

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

[§ 5.2.5] Pre-registration safety data should be obtained in a number of patients sufficient to address the adverse effect profiles of the biosimilar and the Reference Product.

Immunogenicity

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

[§ 5.2.6.3] The immunogenicity of a biosimilar must always be investigated. The assessment of immunogenicity requires an optimal antibody testing strategy, characterization of the observed immune response, as well as evaluation of the correlation between antibodies and PK or PD. It is important to separately consider the risk of immunogenicity in different therapeutic indications.

[§ 5.2.6.4] The applicant should present a rationale for the proposed antibody testing strategy. Testing for immunogenicity should be performed by state-of-the-art methods using assays with appropriate specificity and sensitivity. Standard methods and international standards should be used whenever possible.

[§ 5.2.6.5] Special consideration should be given to those products where there is a chance that the immune response could seriously affect the endogenous protein and its unique biological function. Antibody testing should be considered as part of all clinical trial protocols. The applicant should consider the role of immunogenicity in certain events, such as hypersensitivity, infusion reactions, autoimmunity, and loss of efficacy.

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.

Not addressed.

Risk Management Plans

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

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

[§ 5.2.5] Data from pre-registration clinical studies are normally insufficient to identify all potential differences. Clinical safety of biosimilars must, therefore, be monitored closely on an ongoing basis during the post-approval phase, including continued benefit-risk assessment.

The applicant should give a risk specification in the application dossier for the product under review. This includes a description of possible safety issues related to tolerability of the biosimilar that may result from a manufacturing process different from that of the Reference Product.

Within the registration procedure the applicant should present a RMP/PV plan similar to the current EU legislation and PV guidelines. This should take into account risks identified during product development and potential risks.

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.

[§ 5.3] Biosimilars are not generic products and cannot be identical to their Reference Products. Further, the formulations may be different, which can have a profound effect on their clinical behavior. In addition, a biosimilar does not necessarily have the same indications or clinical use as the Reference Product.

Therefore, biosimilars cannot be considered interchangeable with the Reference Product or products of the same class. Similarly, automatic substitution cannot apply to biosimilars.

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.

[§ 5.1] Ongoing consideration should be given to the use of emerging technologies (e.g., “real-time” binding assays, genomic/ proteomic microarray sciences) in nonclinical studies.