CBPE

Promoting science based, medically appropriate policies for biologic medicines

Cuba
Number of Biosimilars Available

Not publicly available

Country Spotlight: Cuba

Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Médicos (CECMED), is the regulatory body for approval of medicines in Cuba, including the scientific evaluation of biologics and biosimilars. CECMED comes under the authority of The Ministry of Public Health, also known as Ministerio de Salud Pública.

In Cuba, biosimilars are called Known Biosimilar Products.

Biosimilars Available

Not publicly available.

Score Overview

Cuba is Partially Compliant.

The WHO guidance was compared to the relevant sections across the CECMED guidelines resulting in an overall score for Cuba is 3.03/5. This means the CECMED guidances are partially or fully compliant with WHO in some areas, but in some 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 eleven areas where CECMED 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 CECMED guidelines do not specify that the same host cell should be used to produce the medicine.

Gap 2

Route of Administration:

This topic is not addressed by the CECMED guidelines.

Gap 3

Quality/analytical, Isolation of Drug Substance:

The appropriate outcome of tests used to evaluate isolation of drug substance (the active ingredient of a biologic medicine) is not specified.

Gap 4

Quality/Analytical, Stability Studies:

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

Gap 5

Nonclinical, Pharmacology (in vivo and in vitro):

The guidelines do not provide the level of specificity and detail provided by the WHO on how to conduct in vitro studies.

Gap 6

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 7

Clinical, Safety:

The guidelines do not provide the same degree of specificity as WHO regarding an evaluation of biosimilar clinical safety.

Gap 8

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 9

Interchangeability:

This topic is not addressed by the CECMED guidelines.

Gap 10

Naming:

This topic is not addressed by the CECMED guidelines.

Gap 11

Labeling:

This topic is not addressed by the CECMED guidelines.

Overall country score as compared to peers

History of Policy

CECMED published their biosimilar guidelines in 2011. They are based on WHO guidances with some differences that ensure the guidelines are appropriately tailored to Cuba.

Policy Guidelines

Requirements for Marketing Authorization of Known Biological 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 2011; Most recent update 2011

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.

[§ 1.6] Includes domestic or imported biological products with active ingredients “obtained by recombinant DNA techniques (recombinant proteins or monoclonal antibodies).”

[§ 1.7] Excludes prophylactic vaccines and hemoderivatives, including their recombinant analogues, which are governed by regulations specific to those products.

Section 9 provides guidance on requirements for biosimilar monoclonal antibody products. This chart does not reflect this product-specific guidance.

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.

[§ 2.3] A biosimilar is a product that has an active ingredient with a structure and a safety and efficacy profile comparable to that of the Reference Product.

[§ 10] A biosimilar will be approved if comparability between the quality, safety, and efficacy of the biosimilar and the Reference Product is demonstrated and detected differences do not negatively affect the product’s safety and efficacy profile.

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.

[§§ 2.3, 2.4] An reference product is a biological product registered as a new drug product in Cuba or another country on the basis of quality, nonclinical, and complete clinical information.

[§ 6.1] A biosimilar cannot serve as an reference product.

[§ 6.2] It is preferable for the reference product to be registered in Cuba.

[§ 6.3] If the reference product is not registered in Cuba, it must be registered in a country with experience with manufacturing, control, regulation, and post-market surveillance of products, or registered by an authority certified as “Reference” by the Pan-American Health Organization.

[§ 6.4] The applicant must present the justification for the reference product selection.

[§ 6.5] The same reference product must be used in all comparability studies.

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.

[§ 5.2] An applicant must demonstrate that the excipients do not interfere with quality determinations.

[§ 5.5] If the biosimilar uses a different formulation than that of the Reference Product, an application must include information about the effect on product quality, safety, and efficacy.

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.

[§ 2.3] The dosage form and strength or 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.

[§§ 4.5, 8 ] The scope and complexity of clinical (and nonclinical) information required depends on the knowledge about the Reference Product, the pharmacological classification, the indication, and the differences detected during the comparative analytical characterization.

[§ 8.1] Clinical study information should include a risk evaluation comparing the biosimilar and Reference Product with regard to quality, safety, and efficacy, based on studies of the Reference Product in the literature and clinical results obtained for the biosimilar.

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.

[§ 5.2] If an isolation method is used, it must be described.

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] Comparative studies must characterize the physicochemical properties of the biosimilar and the Reference Product. Detected differences must be justified.

[§ 5.4] The applicant must provide information about: (1) physicochemical properties such as molecular weight, isoforms pattern, extinction coefficient or molar absorptivity, and electrophoretic pattern; and (2) structural properties such as primary structure and major higher order structures, amino acids composition, N- and C-terminus information, oligosaccharides pattern, and glycosylation sites.

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

[§ 4.4] In vitro and in vivo studies can demonstrate the absence of functionally significant differences in biological activity between the biosimilar and the Reference Product. For products with multiple activities, several assays must be used with the purpose of evaluating the range of activities.

[§ 5.1] Detected differences in biological activity must be justified.

Immunological

[§ 4.4] The applicant must submit information about the following immunological properties: (1) receptor binding; (2) affinity; (3) avidity; and (4) immunoreactivity, including cross-reactivity. The applicant must identify the complementary region as well as the epitope.

[§ 5.1] Detected differences in immunological properties must be justified.

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.

[§ 5.1] Comparative studies must evaluate purity, impurities, and contaminants. Detected differences must be justified.

[§ 5.4] Purity: the heterogenicity pattern (oxidation, deamidation, glycosylation, etc.) must be compared between the products and consistency must be demonstrated.

[§ 5.4] Impurities: process- and product-related impurities must be identified and quantified. Even though some differences are expected due to differences in the manufacturing processes, the effect of impurities on the biosimilar’s safety and efficacy, including immunogenicity, must be evaluated.

Stability Studies

[§ 8.5] Head-to-head accelerated stability studies will be of value in determining the similarity of the products because they can reveal otherwise-hidden properties of a product that warrant additional evaluation. They are also important for identifying the degradation pathways of a protein product.

[§ 4.4] The expiration period will be established by stability studies conducted under real conditions of temperature and time.

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

[§ 4.4] The biosimilar’s quality specifications must address the quality indices usually evaluated for other biotechnological products (identity, biological activity, purity, impurities, etc.). Specification limits must be established based on manufacturing and analytical experience with the biosimilar. These limits will not necessarily coincide with those established for the Reference Product, due the possible differences between the manufacturing processes and the analytical methods used, but they must not exceed the range in variation of the Reference Product.

General

[§§ 9.1, 9.2] Nonclinical studies should use the final formulation intended for clinical use unless otherwise justified; the nonclinical evaluation encompasses a broad spectrum of PD, PK, and toxicity studies (per ICH S6); the amount of additional nonclinical data for safety and efficacy is dependent on product-specific factors (for example, quality, unknown or poorly understand MoA, significant toxicity, and/or narrow therapeutic index).

[§ 4.5 ] The scope and complexity of nonclinical (and clinical) information required depends on the knowledge about the Reference Product, the pharmacological classification, the requested indication, and the differences detected during the comparative analytical characterization.

[§ 7.1] Nonclinical studies should be chosen in light of quality studies. For example, if there are differences between the biosimilar and the Reference Product, nonclinical evaluations must explore the effect of any differences on efficacy and safety.

Pharmacology

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

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

[§ 7.3] In vivo studies: Comparative studies using the “definitive formulation” should be conducted in animal species sensitive to the PD effects of the product.

[§ 7.4] In vivo and in vitro studies: Comparative PD studies should be conducted to determine strength and biological activity. PD effects must be established by a battery of in vitro and in vivo studies.

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.

[§ 7.4] Comparative PK studies should be conducted to measure bioavailability, half-life, area under the curve, and the duration of PD activities after a single administration. Metabolism and clearance studies are not necessary.

Toxicology

[§ 9.2] Comparative repeat-dose toxicity in relevant species (including TK measurements and antibody responses); local tolerance may need to be evaluated depending on the route of administration.

Safety pharmacology, reproductive toxicology, genotoxicity, and carcinogenicity studies are generally not needed unless cause for concern (based on repeat dose toxicity study or local tolerance study, for example).

[§ 7.4] Studies should be conducted showing the results of repeated administration with one single high dose of both the biosimilar and the Reference Product. TK and surveillance determinations should assess the appearance of antibodies, including appearance time, levels, neutralizing capacity, and cross-reactivity with endogenous proteins or tissues. Information about local tolerance can be obtained as part of other in vivo or toxicological PK studies.

[§ 7.4] The following studies usually will not be required: (1) safety pharmacology; (2) genotoxicity; (3) reproductive effects; and (4) carcinogenicity.

PK and PD

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

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

[§ 8.3] The applicant must report the results of clinical trials describing PD and PK characteristics of the biosimilar.

[§ 8.4] The applicant may present PK and PD studies as the key comparative clinical studies in specific cases (according to the characteristics, use, and therapeutic characteristics of the biological product).

Efficacy Assessment

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

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

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

[§ 8.4] Studies comparing the biosimilar to the Reference Product could be: (1) therapeutic equivalence studies; (2) non-inferiority studies; (3) or PK/PD studies in specific cases (according to the characteristics, use, and therapeutic characteristics of the biologic).

[§ 8.7] For the efficacy demonstration, clinical studies will use “validated subrogated markers for clinical use” reported in the literature concerning the Reference Product.

Safety

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

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

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

[§ 8.6] The applicant must select a sample size that will enable the trial results to reveal the safety of the biosimilar.

Immunogenicity

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

[§ 8.5] The applicant must present immunogenicity data including: (1) levels, class, and sub-class and function of the produced antibodies; (2) appearance time and duration of the titres obtained; (3) immunity induction produced by cells; (4) neutralizing antibodies formation; (5) cross-reaction of antibodies; (6) immunocomplexes formation; (7) other interactions affecting the immune system; and (8) kinetics properties (new excipients and adjuvants).

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.

[§ 10.2, 10.3] A biosimilar will be approved for the “main requested indication” of the Reference Product that was the focus of the comparative clinical studies.

[§ 10.4] Approval of other indications will be evaluated when a comparative clinical study has been completed and on a case-by-case basis. If the (pivotal) clinical study uses a non-comparative design, approval of other indications will require the completion of other clinical trials.

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).

[§ 4.6] The applicant must submit an RMP and a “chronology” for active post-market surveillance, taking into consideration identified and potential risks.

[§ 11.1] After product registration, the applicant must present annual reports (pursuant to Cuban regulations concerning good manufacturing practices for pharmaceutical products) as well as safety reports.

[§ 11.2] Post-market surveillance must be developed according to current regulatory regulations. Traceability must be ensured by international common denomination, product name, lot number, manufacturer, and owner.

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.

[§ 3.6] Good Manufacturing Practices regulations must be followed guaranteeing that both the active ingredient and the finished product are consistently produced and controlled.

[§ 5.3] Applicants should use a battery of analytic tests, such that a method can detect differences that others cannot.