- Email: [email protected]
The regulatory framework for similar biotherapeutic products in Cuba
Biologicals 39 (2011) 317e320
Contents lists available at SciVerse ScienceDirect
Biologicals journal homepage: www.elsevier.com/locate/biologicals
The regulatory framework for similar biotherapeutic products in Cuba Yanet Hechavarría Núñez*, Rodrigo Omar Pérez Massipe, Santa Deybis Orta Hernández, Lázara Martínez Muñoz, Olga Lidia Jacobo Casanueva, Violeta Pérez Rodríguez, Rolando Bárbaro Domínguez Morales, Rafael B. Pérez Cristiá Centro para el Control Estatal de la Calidad de los Medicamentos (CECMED), Calle 200 No.1706 e/17 y 19, Reparto Siboney, CP 11600, Apdo. Postal 16065, Ciudad de La Habana, Cuba1
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 August 2011
Biopharmaceuticals make up a significant proportion of medicinal products used for the treatment of diseases such as cancer, arthritis, cardiac dysfunctions and AIDS. Access to therapies based on the use of these products has been limited as a result of the high marketing costs. Cuba has a biopharmaceutical industry with great potential for innovation, capable of developing new products and to produce others, like the biosimilars destined to fulfill the needs of its National Health System. The Center for State Control on the Quality of Drugs (CECMED) the Cuban NRA, is facing the challenge of regulating the approval of biosimilar products manufactured locally. Consequently, CECMED has issued a position paper establishing the basic principles for regulation of these products and a specific guideline on this was elaborated. Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.
Keywords: Known biological product CECMED Polo Científico del Oeste de La Habana Similar biotherapeutic product
1. Introduction
2. National context
Recombinant proteins and monoclonal antibodies represent a significant proportion of the medicinal products used for the treatment of diseases such as cancer, arthritis, cardiac dysfunction and AIDS. Access to therapies based on the use of biological products has been limited, particularly in the third world countries, as a result of the high costs stipulated by the pharmaceutical companies that have developed and patented these products. The expiration of patents and data protection for many of these products in the coming years opens the opportunity for other manufacturers to produce and market, with acceptable prices, new versions of the innovator, facilitating the access to them, which in turn translates into greater benefit for patients. Therefore, it is imperative that National Regulatory Authorities (NRA) adopt positions and establish the corresponding regulatory environment for these products. Cuba has a biopharmaceutical industry capable of responding to the increasingly rising needs of its National Health System. During the last two decades, CECMED has faced the challenge of regulating a national industry with a great scientific and high innovative potential and now is dealing with the approval of biosimilar products locally manufactured.
Highly developed science parks (SP) have played an important role in the scientific and technology development. In many cases, like in Cuba, these are scientific organizations that link science, manufacturing and services altogether. This is particular relevant in the field of the biotechnology and medical e pharmaceutical industry [1]. In the case of Cuba, the science park of western Havana (in spanish “Polo Científico del Oeste de La Habana”) was created as an organizational unit in 1990. It brings together various institutions on the basis of a strategy of a “closed loop”, covering all stages of research, development, production and marketing of a product. Some institutions work in a great diversity of areas (e.g. vaccines, rDNA products, agricultural products, etc), others are more focused on specific topics (e.g. molecular immunology) [1]. These institutions possess trained and experienced staff, including scientists and health professionals. The Center for Genetic Engineering and Biotechnology, the Center for Molecular Immunology, the Finlay Institute are some of the institutions of the science park of the western Havana. For the last twenty years the science park of the western Havana has sustained a growth in scientificetechnological activity, particularly from 1998. Different products have been developed and introduced into the Cuban market, and also exported to others countries. Most of them are medicinal products for human use, such as vaccines, cytokines and monoclonal antibodies but culture media, veterinary medicinal products, diagnostics and medical
* Corresponding author. Tel.: þ537 271 8645; fax: þ537 271 4023. E-mail address: [email protected] (Y. Hechavarría Núñez). 1 [email protected].
1045-1056/$36.00 Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article. doi:10.1016/j.biologicals.2011.08.005
318
Y. Hechavarría Núñez et al. / Biologicals 39 (2011) 317e320
equipment are also included. But the main roles have been the contribution to the control of infectious diseases, in the increase of the life expectancy and in the reduction of infant mortality [2]. Up until October 2010, 133 biological products have been licensed, of which 67 are locally manufactured. For locally produced approved products, vaccines are the largest product type followed by alfa interferon and blood derivatives, whilst for imported products, insulins as well as pegylated compounds ranked first, followed by vaccines (Fig. 1) [3]. It should be highlighted that local products are mostly produced by a unique manufacturer. However, the same imported product is usually manufactured by more than one company. Monoclonal antibodies are an interesting case because there are only 4 imported products (Mabthera rituximab, Herceptin trastuzumab, Avastin bevacizumab, Simulet basiliximab) and 1 locally manufactured (CIMAher nimotuzumab) product approved [3]. However, cancer has been the second leading cause of death for the whole Cuban population for more than three decades and the leading cause of premature mortality [4,5]. Consequently health authorities have allocated resources and efforts for patients suffering from this disease. But in 2009, for instance, only the 64%, 15% and 5% of Mabthera, Herceptin and Avastin respectively, of the real patient needs were imported, which is clearly insufficient to treat all patients reported in the country. For this reason, one of the main objectives of the cancer control program is to expand local production of products for oncology use (cytostatics, support products and new biotechnology products) 3 [4] and the pipeline of the science park of the western Havana for the next decade incorporates the production of cancer therapeutic vaccines and similar monoclonal antibodies. 3. Regulatory framework in Cuba The legal basis for marketing authorization of medicinal products is based on the Ministerial Resolution “Rules for Marketing
Authorization of Medicinal Products for Human Use” [6]. This document sets up the classification of medicinal products in different categories according to their degree of novelty. Traditionally biological and biotechnological products were included in category A, with the greatest degree of novelty. After several years of implementation of these classification criteria, CECMED identified the need to redesign it, taking into account the evidence at the level of quality, safety and efficacy, as well as the time the product has been in the market and therapeutic effect of the products. As a result, the rules for marketing authorization were updated on 2009 and new classes and classification categories were defined (Table 1). The new classification categories consider three basic concepts: the definition well delimited of two classes of medicinal products: new and known; the period of use in the international and/or national market of the medicinal product and the inclusion of biological products within the class of known medicinal products. Moreover, the information to be submitted for marketing authorization application is described in the Ministerial Resolution “Requirements for Marketing Authorization, Renewal and Variation Applications of Medicinal Products for Human Use” [7]. This document is divided as follows: Information for Drugs and Information for Biological/Biotechnological products. The volume of data to be presented depends on the category of its classification. That is, for a category A product a full dossier is required for quality, non-clinical and clinical information whereas for a category C product, a reduced data package could be accepted particularly for non-clinical and clinical information. Most of the biological products were licensed on a basis of a full dossier for quality, non-clinical and clinical data. Nevertheless some products were approved considering comparability information for non-clinical and/or clinical data. That is the case of a recombinant erythropoietin locally manufactured, which was approved in 2004. The application included information related to comparative studies developed for non-clinical and clinical information using
Fig. 1. Comparison between the number of local and imported licensed biological products: by type of products vaccines, alfa interferon and blood derivatives are most for local manufactured biologicals. For imported products, insulin and pegylated compounds ranked first, followed by vaccines PEG-compounds: pegilated compounds Others: includes kits (combination of products) and products obtained from human placenta, animal tissues.
Required e Equivalence. e Non inferiority. e Non comparative (case-by-case, e.g. Mabs). e Required for quality and non-clinical data. e Required clinical data but not always. Known biological product: A biological product produced by multiple manufacturers, in which the active substance is comparable in terms of quality, safety and efficacy profiles to the API of an already licensed biological product(biological reference product) in Cuba or in other countries. The dosage form, strength/concentration/potency and indications should be the same as that of the biological reference product.
Required e Equivalence. e Non inferiority. Required for quality, non-clinical and clinical data. A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product.
CECMED
Clinical Trial design Comparability information Similar Biotherapeutic Product
319
A product used as the comparator for head-to-head comparability studies with the similar biotherapeutic product in order to show similarity in terms of quality, safety and efficacy. Only an originator product that was licensed on the basis of a full registration dossier can serve as an RBP. A product used as the comparator for comparability studies. Licensed following assessment of a full quality, safety and efficacy data package. Should be licensed in Cuba or: e Licensed in countries with experience in manufacturing, control, regulation and post-marketing surveillance activities for biological/biotechnological products. e Authorized by NRAs of the region of Americas that has passed the evaluation process carried out by PAHO (NRAs considered “matured” in the regulation and control of biological /biotechnological products).
Class 1. New Medicinal Product: Requires demonstration of quality, safety and efficacy and has been marketed for less than five years. Are divided into two categories Category A New molecular entity. Category B New salt, ester, isomer, dosage form, administration route, drug substances association. Class 2. Known Medicinal Product: Requires demonstration of quality, as well as elements of safety, efficacy or therapeutic equivalence, when applicable, and has been marketed for more than five years. Are grouped into one category: Category C Multisource medicinal products, including biological products, which present the same drug substance, dosage form, strength or concentration and indications of other medicinal products, already licensed in Cuba or another country.
WHO
Table 1 Classification categories for medicinal products established on the Rules for Marketing Authorization.
Reference product
Regarding the products included on category C, there is a particular case for biological products that claim to be similar to an already approved biological product. In this case the term known biological product instead biosimilar was adopted in Cuba, as this term is defined in our regulations. It was also taken into account that biological products are considered molecules of highly structural complexity and very sensitive to important variations in their also complex manufacturing process. However, despite of these facts, the scientific and technical advances in the characterization of these molecules has allowed scientist monitoring and identifiying potential modifications in their molecular structure. This may lead to a new approach when defining new and known biological products. Although the rules for marketing authorization establish the legal basis for the approval of known biological products, there is not yet any biological product approved under this category. In March, 2009 a position paper was issued, defining the general strategy to be followed for the approval of a known biological product. A working group was also created, comprising NRA and industry staff, charged with discussing scientific and regulatory issues on known biological products. The main issues identified were related to clinical trial design (equivalence vs non-inferiority vs non-comparative); quality and non-clinical information required for known biological products, particularly Mabs, and whether the reference product must be licensed in Cuba and the strategy to be adopted when it is not licensed in our country. Specific guidelines were developed taking into account the experience accumulated by CECMED, as a result of the evaluation of applications for clinical trials and marketing authorizations of the biological products approved in Cuba, the assessment of comparability studies submitted due to manufacturing process changes and non-clinical and clinical comparability studies conducted in the country. The findings generated from the debate in the working group were also considered.
Definitions
4. Similar biotherapeutic products
Table 2 Similarities and differences between Cuban and WHO guidelines. The main differences are observed in the definition of biotherapeutic reference product and the design of clinical trials to be used.
EPREX, a product not licensed in Cuba as comparator, while for quality a stand-alone approach was adopted. Other guidelines concerning the development of stability studies, validation of analytical assays and the characterization of reference materials, amongst others, are available [8] because all functions are covered by a regulatory system based on laws, regulations, decisions and procedures. Additionally, recommendations from WHO, ICH and PARF network are also considered, as well as some specific guidelines issued by FDA and EMA.
Post-marketing active surveillance
Y. Hechavarría Núñez et al. / Biologicals 39 (2011) 317e320
320
Y. Hechavarría Núñez et al. / Biologicals 39 (2011) 317e320
In general, the guideline took into account the following principles: - A full dossier is requested for quality, according to the requirements for marketing authorization approval in force. An additional section comprising all the information relating to comparative studies conducted for the known biological product with the biological reference product should be submitted. This section will include data on the determination of physicochemical, biological activity, immunological properties, purity and impurities and contaminants, and other tests that could be considered necessary (e.g, pH and osmolality of the final product). - The magnitude and complexity of non-clinical and clinical data will depend on the existing knowledge about the biological reference product, pharmacological classification, the claimed therapeutic indication as well as the differences detected during the quality comparative characterization. Non-clinical information should include results of comparative studies for biological activity, bioavailability and single-dose toxicity studies. Local tolerance and immunogenicity data will be also requested. - For the clinical data, a detailed analysis of safety studies reported for the biological reference product and those conducted for the known biological product should be presented. Also, results of efficacy clinical trials should be included; the design of this can be equivalence, non-inferiority or noncomparative, but the choice should be justified. A noncomparative study is an exceptional case, for molecules like monoclonal antibodies, where a comparative trial might be not feasible due to heterogeneity in the response of the patient population would require a higher number of patients to prove similarity. This choice will be analyzed case-by-case. All clinical trials carried out for the known biological product to support the marketing authorization application should be previously authorized by CECMED. - A specific section of information is added for similar monoclonal antibodies, given particular characteristics of these molecules. - A risk management program/active post-marketing surveillance plan should be also presented. - The Reference Biological Product should be licensed based on full quality, safety, and efficacy data. This product should preferably be approved in Cuba. However, as Cuba is a country with a small market, it is possible that the RBP may not be licensed. In this case, the applicant has two choices: select a product licensed in countries with experience in manufacturing, control, regulation and post-marketing surveillance activities for biological/biotechnological products or a product authorized by NRAs of the region of Americas that
has passed the evaluation process carried out by PAHO (these are NRAs that has been considered “matured” in the regulation and control of biological/biotechnological products). The rationale for RBP selection should always be presented. Some general principles established in the WHO guidelines for similar biotherapeutic products [9] were considered. However, there are some differences between the WHO and the Cuban guidelines (Table 2). The first draft of the Cuban guideline was released for regulatory consultation during October and November 2010 [10]. It is expected to have the final document approved during the first semester of 2011. Conflict of interest The authors have disclosed no potential conflicts of interests. Acknowledgements The authors would like to thank scientists and specialists from the Center of Molecular Immunology, Center for Genetic Engineering and Biotechnology, Roche and IFPMA for their comments and opinions on CECMED’s known biological products draft guideline. References [1] Guzmán MV, Milanés Y, Martínez T, Carrillo H. Identificación de las estrategias tecnológicas de los Polos Científicos: estudio comparativo por áreas geográficas [consulted on October 13], www.bibliociencias.cu/gsdl/collect/ eventos/index/assoc/HASH3edb.dir/doc.pdf; 2010. [2] Herreros F. Las Razones del Desarrollo Científico Cubano [consulted on October 13], www.nodo50.org/cesc/Documentos/DesarrolloCientificoCubano. pdf; 2010. [3] Cecmed, List of licensed products, www.cecmed.sld.cu/Pages/RegSan.htm. [4] Camacho Rodríguez R. Esperanza de vida y cáncer en Cuba [consulted on October 13], www.sld.cu/galerias/pdf/sitios/gericuba/rolando_camacho.pdf; 2010. [5] Sansó Soberats FJ, Alonso Galbán P, Torres Vidal RM. Mortality from cancer in Cuba. Revista Cubana de Salud Pública 2010;36(1):78e94 [consulted on October 13, 2010], www.scielosp.org/scielo.php?script¼sci_arttext&; pid¼S0864-34662010000100009. [6] MINSAP. Resolution 321 rules for marketing authorization of medicinal products for human use, www.cecmed.sld.cu/Pages/Reg_LicProd-3.htm; 2009. [7] MINSAP. Resolution 168 requirements for marketing authorization, Renewal and variation applications of medicinal products for human use, www. cecmed.sld.cu/Pages/Reg_LicProd.htm; 2000. [8] CECMED, Approved regulations www.cecmed.sld.cu/Pages/DRA.htm. [9] WHO/ECBS. Guidelines on evaluation of similar biotherapeutic products (SBPS), www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPE UTICS_FOR_WEB_22APRIL2010.pdf; 2010. [10] CECMED. Requirements for marketing authorization of known biological products DRAFT 1st VERSION, www.cecmed.sld.cu/Pages/PDRC.htm; October 2010.
Contents lists available at SciVerse ScienceDirect
Biologicals journal homepage: www.elsevier.com/locate/biologicals
The regulatory framework for similar biotherapeutic products in Cuba Yanet Hechavarría Núñez*, Rodrigo Omar Pérez Massipe, Santa Deybis Orta Hernández, Lázara Martínez Muñoz, Olga Lidia Jacobo Casanueva, Violeta Pérez Rodríguez, Rolando Bárbaro Domínguez Morales, Rafael B. Pérez Cristiá Centro para el Control Estatal de la Calidad de los Medicamentos (CECMED), Calle 200 No.1706 e/17 y 19, Reparto Siboney, CP 11600, Apdo. Postal 16065, Ciudad de La Habana, Cuba1
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 August 2011
Biopharmaceuticals make up a significant proportion of medicinal products used for the treatment of diseases such as cancer, arthritis, cardiac dysfunctions and AIDS. Access to therapies based on the use of these products has been limited as a result of the high marketing costs. Cuba has a biopharmaceutical industry with great potential for innovation, capable of developing new products and to produce others, like the biosimilars destined to fulfill the needs of its National Health System. The Center for State Control on the Quality of Drugs (CECMED) the Cuban NRA, is facing the challenge of regulating the approval of biosimilar products manufactured locally. Consequently, CECMED has issued a position paper establishing the basic principles for regulation of these products and a specific guideline on this was elaborated. Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.
Keywords: Known biological product CECMED Polo Científico del Oeste de La Habana Similar biotherapeutic product
1. Introduction
2. National context
Recombinant proteins and monoclonal antibodies represent a significant proportion of the medicinal products used for the treatment of diseases such as cancer, arthritis, cardiac dysfunction and AIDS. Access to therapies based on the use of biological products has been limited, particularly in the third world countries, as a result of the high costs stipulated by the pharmaceutical companies that have developed and patented these products. The expiration of patents and data protection for many of these products in the coming years opens the opportunity for other manufacturers to produce and market, with acceptable prices, new versions of the innovator, facilitating the access to them, which in turn translates into greater benefit for patients. Therefore, it is imperative that National Regulatory Authorities (NRA) adopt positions and establish the corresponding regulatory environment for these products. Cuba has a biopharmaceutical industry capable of responding to the increasingly rising needs of its National Health System. During the last two decades, CECMED has faced the challenge of regulating a national industry with a great scientific and high innovative potential and now is dealing with the approval of biosimilar products locally manufactured.
Highly developed science parks (SP) have played an important role in the scientific and technology development. In many cases, like in Cuba, these are scientific organizations that link science, manufacturing and services altogether. This is particular relevant in the field of the biotechnology and medical e pharmaceutical industry [1]. In the case of Cuba, the science park of western Havana (in spanish “Polo Científico del Oeste de La Habana”) was created as an organizational unit in 1990. It brings together various institutions on the basis of a strategy of a “closed loop”, covering all stages of research, development, production and marketing of a product. Some institutions work in a great diversity of areas (e.g. vaccines, rDNA products, agricultural products, etc), others are more focused on specific topics (e.g. molecular immunology) [1]. These institutions possess trained and experienced staff, including scientists and health professionals. The Center for Genetic Engineering and Biotechnology, the Center for Molecular Immunology, the Finlay Institute are some of the institutions of the science park of the western Havana. For the last twenty years the science park of the western Havana has sustained a growth in scientificetechnological activity, particularly from 1998. Different products have been developed and introduced into the Cuban market, and also exported to others countries. Most of them are medicinal products for human use, such as vaccines, cytokines and monoclonal antibodies but culture media, veterinary medicinal products, diagnostics and medical
* Corresponding author. Tel.: þ537 271 8645; fax: þ537 271 4023. E-mail address: [email protected] (Y. Hechavarría Núñez). 1 [email protected].
1045-1056/$36.00 Ó World Health Organization 2011. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article. doi:10.1016/j.biologicals.2011.08.005
318
Y. Hechavarría Núñez et al. / Biologicals 39 (2011) 317e320
equipment are also included. But the main roles have been the contribution to the control of infectious diseases, in the increase of the life expectancy and in the reduction of infant mortality [2]. Up until October 2010, 133 biological products have been licensed, of which 67 are locally manufactured. For locally produced approved products, vaccines are the largest product type followed by alfa interferon and blood derivatives, whilst for imported products, insulins as well as pegylated compounds ranked first, followed by vaccines (Fig. 1) [3]. It should be highlighted that local products are mostly produced by a unique manufacturer. However, the same imported product is usually manufactured by more than one company. Monoclonal antibodies are an interesting case because there are only 4 imported products (Mabthera rituximab, Herceptin trastuzumab, Avastin bevacizumab, Simulet basiliximab) and 1 locally manufactured (CIMAher nimotuzumab) product approved [3]. However, cancer has been the second leading cause of death for the whole Cuban population for more than three decades and the leading cause of premature mortality [4,5]. Consequently health authorities have allocated resources and efforts for patients suffering from this disease. But in 2009, for instance, only the 64%, 15% and 5% of Mabthera, Herceptin and Avastin respectively, of the real patient needs were imported, which is clearly insufficient to treat all patients reported in the country. For this reason, one of the main objectives of the cancer control program is to expand local production of products for oncology use (cytostatics, support products and new biotechnology products) 3 [4] and the pipeline of the science park of the western Havana for the next decade incorporates the production of cancer therapeutic vaccines and similar monoclonal antibodies. 3. Regulatory framework in Cuba The legal basis for marketing authorization of medicinal products is based on the Ministerial Resolution “Rules for Marketing
Authorization of Medicinal Products for Human Use” [6]. This document sets up the classification of medicinal products in different categories according to their degree of novelty. Traditionally biological and biotechnological products were included in category A, with the greatest degree of novelty. After several years of implementation of these classification criteria, CECMED identified the need to redesign it, taking into account the evidence at the level of quality, safety and efficacy, as well as the time the product has been in the market and therapeutic effect of the products. As a result, the rules for marketing authorization were updated on 2009 and new classes and classification categories were defined (Table 1). The new classification categories consider three basic concepts: the definition well delimited of two classes of medicinal products: new and known; the period of use in the international and/or national market of the medicinal product and the inclusion of biological products within the class of known medicinal products. Moreover, the information to be submitted for marketing authorization application is described in the Ministerial Resolution “Requirements for Marketing Authorization, Renewal and Variation Applications of Medicinal Products for Human Use” [7]. This document is divided as follows: Information for Drugs and Information for Biological/Biotechnological products. The volume of data to be presented depends on the category of its classification. That is, for a category A product a full dossier is required for quality, non-clinical and clinical information whereas for a category C product, a reduced data package could be accepted particularly for non-clinical and clinical information. Most of the biological products were licensed on a basis of a full dossier for quality, non-clinical and clinical data. Nevertheless some products were approved considering comparability information for non-clinical and/or clinical data. That is the case of a recombinant erythropoietin locally manufactured, which was approved in 2004. The application included information related to comparative studies developed for non-clinical and clinical information using
Fig. 1. Comparison between the number of local and imported licensed biological products: by type of products vaccines, alfa interferon and blood derivatives are most for local manufactured biologicals. For imported products, insulin and pegylated compounds ranked first, followed by vaccines PEG-compounds: pegilated compounds Others: includes kits (combination of products) and products obtained from human placenta, animal tissues.
Required e Equivalence. e Non inferiority. e Non comparative (case-by-case, e.g. Mabs). e Required for quality and non-clinical data. e Required clinical data but not always. Known biological product: A biological product produced by multiple manufacturers, in which the active substance is comparable in terms of quality, safety and efficacy profiles to the API of an already licensed biological product(biological reference product) in Cuba or in other countries. The dosage form, strength/concentration/potency and indications should be the same as that of the biological reference product.
Required e Equivalence. e Non inferiority. Required for quality, non-clinical and clinical data. A biotherapeutic product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product.
CECMED
Clinical Trial design Comparability information Similar Biotherapeutic Product
319
A product used as the comparator for head-to-head comparability studies with the similar biotherapeutic product in order to show similarity in terms of quality, safety and efficacy. Only an originator product that was licensed on the basis of a full registration dossier can serve as an RBP. A product used as the comparator for comparability studies. Licensed following assessment of a full quality, safety and efficacy data package. Should be licensed in Cuba or: e Licensed in countries with experience in manufacturing, control, regulation and post-marketing surveillance activities for biological/biotechnological products. e Authorized by NRAs of the region of Americas that has passed the evaluation process carried out by PAHO (NRAs considered “matured” in the regulation and control of biological /biotechnological products).
Class 1. New Medicinal Product: Requires demonstration of quality, safety and efficacy and has been marketed for less than five years. Are divided into two categories Category A New molecular entity. Category B New salt, ester, isomer, dosage form, administration route, drug substances association. Class 2. Known Medicinal Product: Requires demonstration of quality, as well as elements of safety, efficacy or therapeutic equivalence, when applicable, and has been marketed for more than five years. Are grouped into one category: Category C Multisource medicinal products, including biological products, which present the same drug substance, dosage form, strength or concentration and indications of other medicinal products, already licensed in Cuba or another country.
WHO
Table 1 Classification categories for medicinal products established on the Rules for Marketing Authorization.
Reference product
Regarding the products included on category C, there is a particular case for biological products that claim to be similar to an already approved biological product. In this case the term known biological product instead biosimilar was adopted in Cuba, as this term is defined in our regulations. It was also taken into account that biological products are considered molecules of highly structural complexity and very sensitive to important variations in their also complex manufacturing process. However, despite of these facts, the scientific and technical advances in the characterization of these molecules has allowed scientist monitoring and identifiying potential modifications in their molecular structure. This may lead to a new approach when defining new and known biological products. Although the rules for marketing authorization establish the legal basis for the approval of known biological products, there is not yet any biological product approved under this category. In March, 2009 a position paper was issued, defining the general strategy to be followed for the approval of a known biological product. A working group was also created, comprising NRA and industry staff, charged with discussing scientific and regulatory issues on known biological products. The main issues identified were related to clinical trial design (equivalence vs non-inferiority vs non-comparative); quality and non-clinical information required for known biological products, particularly Mabs, and whether the reference product must be licensed in Cuba and the strategy to be adopted when it is not licensed in our country. Specific guidelines were developed taking into account the experience accumulated by CECMED, as a result of the evaluation of applications for clinical trials and marketing authorizations of the biological products approved in Cuba, the assessment of comparability studies submitted due to manufacturing process changes and non-clinical and clinical comparability studies conducted in the country. The findings generated from the debate in the working group were also considered.
Definitions
4. Similar biotherapeutic products
Table 2 Similarities and differences between Cuban and WHO guidelines. The main differences are observed in the definition of biotherapeutic reference product and the design of clinical trials to be used.
EPREX, a product not licensed in Cuba as comparator, while for quality a stand-alone approach was adopted. Other guidelines concerning the development of stability studies, validation of analytical assays and the characterization of reference materials, amongst others, are available [8] because all functions are covered by a regulatory system based on laws, regulations, decisions and procedures. Additionally, recommendations from WHO, ICH and PARF network are also considered, as well as some specific guidelines issued by FDA and EMA.
Post-marketing active surveillance
Y. Hechavarría Núñez et al. / Biologicals 39 (2011) 317e320
320
Y. Hechavarría Núñez et al. / Biologicals 39 (2011) 317e320
In general, the guideline took into account the following principles: - A full dossier is requested for quality, according to the requirements for marketing authorization approval in force. An additional section comprising all the information relating to comparative studies conducted for the known biological product with the biological reference product should be submitted. This section will include data on the determination of physicochemical, biological activity, immunological properties, purity and impurities and contaminants, and other tests that could be considered necessary (e.g, pH and osmolality of the final product). - The magnitude and complexity of non-clinical and clinical data will depend on the existing knowledge about the biological reference product, pharmacological classification, the claimed therapeutic indication as well as the differences detected during the quality comparative characterization. Non-clinical information should include results of comparative studies for biological activity, bioavailability and single-dose toxicity studies. Local tolerance and immunogenicity data will be also requested. - For the clinical data, a detailed analysis of safety studies reported for the biological reference product and those conducted for the known biological product should be presented. Also, results of efficacy clinical trials should be included; the design of this can be equivalence, non-inferiority or noncomparative, but the choice should be justified. A noncomparative study is an exceptional case, for molecules like monoclonal antibodies, where a comparative trial might be not feasible due to heterogeneity in the response of the patient population would require a higher number of patients to prove similarity. This choice will be analyzed case-by-case. All clinical trials carried out for the known biological product to support the marketing authorization application should be previously authorized by CECMED. - A specific section of information is added for similar monoclonal antibodies, given particular characteristics of these molecules. - A risk management program/active post-marketing surveillance plan should be also presented. - The Reference Biological Product should be licensed based on full quality, safety, and efficacy data. This product should preferably be approved in Cuba. However, as Cuba is a country with a small market, it is possible that the RBP may not be licensed. In this case, the applicant has two choices: select a product licensed in countries with experience in manufacturing, control, regulation and post-marketing surveillance activities for biological/biotechnological products or a product authorized by NRAs of the region of Americas that
has passed the evaluation process carried out by PAHO (these are NRAs that has been considered “matured” in the regulation and control of biological/biotechnological products). The rationale for RBP selection should always be presented. Some general principles established in the WHO guidelines for similar biotherapeutic products [9] were considered. However, there are some differences between the WHO and the Cuban guidelines (Table 2). The first draft of the Cuban guideline was released for regulatory consultation during October and November 2010 [10]. It is expected to have the final document approved during the first semester of 2011. Conflict of interest The authors have disclosed no potential conflicts of interests. Acknowledgements The authors would like to thank scientists and specialists from the Center of Molecular Immunology, Center for Genetic Engineering and Biotechnology, Roche and IFPMA for their comments and opinions on CECMED’s known biological products draft guideline. References [1] Guzmán MV, Milanés Y, Martínez T, Carrillo H. Identificación de las estrategias tecnológicas de los Polos Científicos: estudio comparativo por áreas geográficas [consulted on October 13], www.bibliociencias.cu/gsdl/collect/ eventos/index/assoc/HASH3edb.dir/doc.pdf; 2010. [2] Herreros F. Las Razones del Desarrollo Científico Cubano [consulted on October 13], www.nodo50.org/cesc/Documentos/DesarrolloCientificoCubano. pdf; 2010. [3] Cecmed, List of licensed products, www.cecmed.sld.cu/Pages/RegSan.htm. [4] Camacho Rodríguez R. Esperanza de vida y cáncer en Cuba [consulted on October 13], www.sld.cu/galerias/pdf/sitios/gericuba/rolando_camacho.pdf; 2010. [5] Sansó Soberats FJ, Alonso Galbán P, Torres Vidal RM. Mortality from cancer in Cuba. Revista Cubana de Salud Pública 2010;36(1):78e94 [consulted on October 13, 2010], www.scielosp.org/scielo.php?script¼sci_arttext&; pid¼S0864-34662010000100009. [6] MINSAP. Resolution 321 rules for marketing authorization of medicinal products for human use, www.cecmed.sld.cu/Pages/Reg_LicProd-3.htm; 2009. [7] MINSAP. Resolution 168 requirements for marketing authorization, Renewal and variation applications of medicinal products for human use, www. cecmed.sld.cu/Pages/Reg_LicProd.htm; 2000. [8] CECMED, Approved regulations www.cecmed.sld.cu/Pages/DRA.htm. [9] WHO/ECBS. Guidelines on evaluation of similar biotherapeutic products (SBPS), www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPE UTICS_FOR_WEB_22APRIL2010.pdf; 2010. [10] CECMED. Requirements for marketing authorization of known biological products DRAFT 1st VERSION, www.cecmed.sld.cu/Pages/PDRC.htm; October 2010.