Source: https://biologicspolicy.com/country/cuba
Timestamp: 2020-01-25 04:22:10
Document Index: 795374995

Matched Legal Cases: ['§ 1', '§ 1', '§ 2', '§ 10', '§ 2', '§ 6', '§ 6', '§ 6', '§ 6', '§ 6', '§ 5', '§ 5', '§ 2', '§ 4', '§ 8', '§ 5', '§ 5', '§ 5', '§ 4', '§ 5', '§ 4', '§ 5', '§ 5', '§ 5', '§ 5', '§ 4', '§ 4', '§ 4', '§ 7', '§ 7', '§ 7', '§ 7', '§ 7', '§ 7', '§ 8', '§ 8', '§ 8', '§ 8', '§ 8', '§ 8', '§ 10', '§ 10', '§ 4', '§ 11', '§ 11', '§ 3', '§ 5']

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.
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.
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.
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.
This topic is not addressed by the CECMED guidelines.
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.
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
The guidelines do not provide the level of specificity and detail provided by the WHO on how to conduct in vitro studies.
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.
Clinical, Safety:
The guidelines do not provide the same degree of specificity as WHO regarding an evaluation of biosimilar clinical safety.
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.
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
[§ 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.
[§ 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.
[§§ 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.
[§ 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.
[§ 2.3] The dosage form and strength or concentration must be the same as that of the Reference Product.
[§§ 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.
[§ 5.2] If an isolation method is used, it must be described.
[§ 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.
[§ 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.
[§ 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.
[§ 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.
[§ 4.4] The expiration period will be established by stability studies conducted under real conditions of temperature and time.
[§ 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.
[§ 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.
[§ 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.
[§ 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.
[§ 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.
[§ 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).
[§ 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.
[§ 8.6] The applicant must select a sample size that will enable the trial results to reveal the safety of the biosimilar.
[§ 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).
[§ 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.
[§ 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.
[§ 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.