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Potential Regulatory and Commercial Environment for Biosimilars in Latin America

      Abstract

      Objectives

      Biosimilars are increasingly attractive to payers around the globe because of mounting financial pressure. Many Latin American governments are developing abbreviated regulatory pathways for biosimilars. There are limited data regarding how certain regulatory agencies in the region plan to address biosimilar access. This study explores potential opportunities and challenges for biosimilar drugs in Brazil, Mexico, Argentina, Chile, and Venezuela.

      Methods

      We conducted targeted literature reviews, followed by key informant interviews, to understand the expected regulatory environment for biosimilars. We also asked questions about the economic, political, and historical factors that could play a role in the extent to which biosimilar-specific pathways have been developed across countries to date, and will continue to evolve in the future.

      Results

      Brazil has led the development of biosimilar regulation in Latin America, with two distinct pathways, one for more complex molecules such as monoclonal antibodies and a less rigorous path for simpler molecules such as pegylated interferon and low molecular weight heparin. Other countries have been slower to respond, in part because of the degree of emphasis within each country for the advancement of biosimilar regulatory standards. Signs of relaxed standards akin to those seen in Brazil's “individual development” pathway were found in other countries.

      Conclusions

      The example of the two-pathway system coupled with governmental prioritization of local manufacturing capabilities in Brazil should promote increased biosimilar utilization within the country. Assuming that the two-pathway system demonstrates success in Brazil, we hypothesize that other Latin American countries may adapt aspects of this “local” model for developing a regulatory pathway for biosimilars.

      Keywords

      Introduction

      The use of biosimilars is increasingly attractive to payers around the globe because of mounting financial pressure from high expenditures on expensive biologics. For example, in Brazil, biotherapeutic products represented 2% of medicines prescribed, yet accounted for 41% of the annual Ministry of Health pharmaceutical budget in 2010 [
      • Castanheira L.G.
      • Barbano D.B.
      • Rech N.
      Current development in regulation of similar biotherapeutic products in Brazil.
      ]. Health agencies view the use of biosimilars as a cost-saving measure that could help alleviate pharmaceutical budgetary concerns. Although biosimilars can potentially have safety, efficacy, or quality concerns, many governments are trying to boost the utilization of biosimilars by developing regulatory channels in hopes of expanding market access.
      In Latin America, many governments have developed or are developing abbreviated regulatory pathways for biosimilars to increase access while enacting sufficient quality standards to ensure safety and efficacy [

      Kirchlechner T. Current regulations of biosimilars in the Latin American region. Paper presented at: 3rd Annual Drug Information Association (DIA) Latin American Regulatory Conference, Panama City, Panama, April 12–15, 2011.

      ]. The World Health Organization (WHO) guidelines for biosimilars, which were finalized in 2009, have been used as a template for many of these countries. These guidelines confirm key principles of biosimilarity, including stand-alone manufacturing process development and demonstrated comparability [
      World Health Organization
      Expert Committee on Biological Standardization.
      ]. There are limited data regarding how national agencies in Latin America plan to address biosimilar access in their respective countries. This study explores potential opportunities and challenges for biosimilar drugs in light of the regulatory environments that exist in Brazil, Mexico, Argentina, Chile, and Venezuela.

      Methods

      For this exploratory study we first conducted online searches, using Google and PubMed, in English, Spanish, and Portuguese to gain an in-depth understanding of the evolution of regulations in each of the five target countries: Argentina, Brazil, Chile, Mexico, and Venezuela. These countries were chosen as representing the leading pharmaceutical markets in Latin America because of their populations and purchasing power (in gross domestic product per capita). We also explored economic, political, and historical factors that could contribute to a higher emphasis on the development of policies to regulate biosimilar products within the respective markets (“Biosimilar Emphasis”).
      We then conducted interviews with an expert informant in each country. Expert informants ranged from officials at federal regulatory agencies responsible for enacting regulation to policy experts and advisors at leading industry organizations within the countries. For each interview, we asked a structured set of questions designed to refine our understanding of what policies currently exist for regulating biosimilar products in each country, and what specific requirements are expected to be enacted in the future to regulate the review and approval of biosimilars. Interviews were conducted in Spanish and Portuguese.
      Findings were analyzed relative to a framework adapted from the work by Dr. Valdair Pinto on biosimilar regulatory pathways in Brazil [

      Pinto V. Biologics and biosimilars in Brazil: regulatory outlook and pharmacoeconomic challenges. In: ISPOR 3rd Latin America Conference. Mexico City, Mexico, September 10, 2011.

      ]. This approach was chosen because it defines a range of potential pathways for regulating biologic drugs ranging from the highest burden of proof for new biological agents to two alternative pathways for follow-on biological products. In the case of the “comparability” alternative pathway, certain categories of information may be substituted with comparative data, while for certain less-complex biosimilars that meet the criteria of the “individual development” pathway (referred to by Pinto as the “desevolvimento individual” pathway), the requirement for certain clinical data may be waived entirely. This spectrum creates a broad framework against which other countries’ potential regulatory requirements for biosimilars can be compared. Our adapted framework is described in Table 1.
      Table 1Potential data requirements/policies for biosimilars.
      Data requirement/policyNew biological productsComparability (biosimilar) pathwayIndividual development (nonbiosimilar) pathway
      Chemistry, manufacturing and controls documentationRequired as for new drugComparative data onlyAccording to developing standards
      Preclinical studiesComparative data with exceptions
      Phase I clinical studiesCan be waived/may not be comparative
      Phase II clinical studiesCan be waived/may not be comparative
      Phase III clinical studiesComparative data with exceptions
      Extrapolation of indicationsYesPossible (with conditions)Not possible
      We also asked questions to supplement our understanding of the level of Biosimilar Emphasis in each country as a result of economic, political, and historical factors that may exist (e.g., governmental programs to develop local industry and/or cut costs, past safety issues with biosimilars). These factors could have played a role in the extent to which biosimilar-specific pathways have been developed across countries to date, and will continue to evolve in the future.
      Market size, degree of interaction with international thought leaders, and local production capabilities were chosen as factors that could contribute to the degree of Biosimilar Emphasis within a country. Market size, for instance, is likely to bring opportunities of scale to capture economic savings through discounted prices that presumably would come with competition from biosimilar products. Countries were categorized into small (<20 million), midsized (20–50 million), or large (>50 million) population. Similarly, interaction with international thought leaders was assumed to be positively correlated with market size, as leading clinicians and academics in larger countries are more likely to be engaged by thought leaders in other countries because of the economic and research opportunities that exist within their market. Finally, local production capabilities was inferred to indicate a greater policy emphasis on biosimilars, because countries that have chosen to develop local production capabilities are more likely to have prioritized the development of a regulatory pathway for the review and approval of locally produced biosimilar products. Of note, market size and interaction with international thought leader categories were defined and assigned subjectively, while the local production categories were assigned on the basis of comments from primary research.
      Throughout, we have used the term “biosimilars” as the most common usage in the English-language literature. However, other terms were noted during our research. For example, biosimilars are frequently referred to as “biologics” in Brazil, as differentiated from “new biologics” to refer to a new branded agent, “biocomparables” in Mexico, or “medicamento biológico similar” in Argentina.

      Results

      The financial pressure to adopt biosimilars in each country is high because biologics consume a sizeable portion of national pharmacy budgets. Nevertheless, each country varies in its propensity to increase access to biosimilars. Findings for each country are detailed below and summarized at the end of the section in two tables. Table 2 contains the current expectations for biosimilar regulation in each country in the context of WHO guidelines. Table 3 lists attributes that could affect a country's policy development pertaining to the regulation of biosimilars.
      Table 2Expected regulatory pathway(s) for biosimilars in five Latin American countries.
      Data requirement/policyWHOBrazilArgentinaChileMexicoVenezuela
      Comparability pathway“Individual development” pathway
      Chemistry, manufacturing and controls documentationComparative data onlyComparative data onlyAccording to developing standardsComparative data onlyRequired as for new drugRequired as for new drugRequired as for new drug
      Preclinical studiesComparative data onlyComparative data with exceptionsComparative data onlyRequired as for new drug
      If a biosimilar product can demonstrate that its base cell culture started proliferation in a similar manner as its originator molecule, then only comparative data will be required.
      Required as for new drug
      Phase I clinical studiesComparative data onlyCan be waived/may not be comparativeRequired as for new drugComparative data only
      Phase II clinical studiesComparative data onlyCan be waived/may not be comparativeComparative data only or required as for new drug, depending on drug typeComparative data only
      Phase III clinical studiesComparative data onlyComparative data with exceptionsComparative data only or not required, depending on drug typeRequired as for new drug in most cases, depending on the molecule
      Extrapolation of indicationsYesYesNoNoPossible once biosimilarity establishedNo, will need to demonstrate efficacy in additional indicationsNo
      WHO, World Health Organization.
      low asterisk If a biosimilar product can demonstrate that its base cell culture started proliferation in a similar manner as its originator molecule, then only comparative data will be required.
      Table 3Attributes potentially affecting the development of biosimilar policies in five Latin American countries.
      AttributeBrazilArgentinaChileMexicoVenezuela
      Market size (population)Large (205 million)Midsized (42 million)Small (17 million)Large (115 million)Midsized (28 million)
      Interaction with international thought leadersHighHighMediumHighMedium
      Local production capabilitiesYesYesYesYesNo
      Safety issues with biosimilars in the pastYes (hematology product(s))NoYes (Wosulin)Yes (Kikuzubam)No
      Expected differences in regulatory requirements based on the complexity of the moleculeYesNAYesYesYes
      Regulatory pathway specific for biosimilarsYesYesNoYesNo
      Year of biosimilar regulatory pathway
      WHO guidelines were finalized in 2009.
      20102005/2011≥20122009 (in development)None
      NA, not available/applicable; WHO, World Health Organization.
      low asterisk WHO guidelines were finalized in 2009.

      Brazil

      Current situation

      In Brazil, the Agência Nacional de Vigilância Sanitária is in charge of regulating biologics and biosimilars. Historically, Brazil had the same regulatory pathway for new biologic products and for copies. However, in 2010, the Agência Nacional de Vigilância Sanitária passed resolution RDC 55/2010, creating new regulatory pathways for new biologic products and biosimilars [
      • Castanheira L.G.
      • Barbano D.B.
      • Rech N.
      Current development in regulation of similar biotherapeutic products in Brazil.
      ]. For biosimilars, two pathways emerged: a “comparability” pathway and an “individual development” pathway. The individual development pathway originated in response to the high government expenditure on pegylated interferon to treat hepatitis C. The Brazilian government sought a lower-cost, high-quality option to relieve budgetary pressure, with the Brazilian government partnering with a Cuban manufacturer (CIGB) to produce pegylated interferon in Brazil. The regulatory requirements were reduced for the new interferon molecule, which was similar to the previously licensed molecule but pegylated using a new technology [
      • Castanheira L.G.
      • Barbano D.B.
      • Rech N.
      Current development in regulation of similar biotherapeutic products in Brazil.
      ]. The success of this project led Brazil to incorporate the individual development pathway into the RDC 55/2010 guidelines, by which clinical requirements can be reduced “depending on the amount of knowledge of pharmacological properties, safety and efficacy of the originator product” [
      • Castanheira L.G.
      • Barbano D.B.
      • Rech N.
      Current development in regulation of similar biotherapeutic products in Brazil.
      ]. This pathway is suitable for certain types of less complex biotherapeutics such as pegylated interferon and low molecular weight heparin [
      • Castanheira L.G.
      • Barbano D.B.
      • Rech N.
      Current development in regulation of similar biotherapeutic products in Brazil.
      ]. In the individual development pathway, the dossier, quality issues, and clinical study requirements are reduced relative to the comparative pathway, and extrapolation of indications is not permitted.
      The comparability pathway is more rigorous and requires comparative phase I, II, and III trials to the originator biological product and will allow extrapolation into other indications. Examples of biotherapeutics that will likely go through this pathway include more complex molecules such as monoclonal antibodies (mAbs). Molecules licensed using the comparability pathway are considered biosimilars. The comparative pathway is almost identical to the WHO Similar Biotherapeutic Products guidelines [
      World Health Organization
      Expert Committee on Biological Standardization.
      ].

      Potential issues

      One issue that could hinder biosimilar uptake is safety. Our primary research suggests that a widely publicized series of adverse events related to a biosimilar could inhibit physician prescribing. Indeed, this has been seen in other countries (see later). In Brazil, however, despite some safety issues with hematology biosimilars in the past, there is no evidence that this affected accessibility to these products.

      Future environment

      Our primary research indicates that biosimilars are expected to have a relatively small discount compared with the originator biologics. Even so, there is a push from the Brazilian government to alleviate biotherapeutic expenditure through the substitution of biosimilars for originator biologics. With government support and local production capabilities, the future commercial outlook for biosimilars in Brazil is positive.

      Mexico

      Current situation

      The regulatory body for approval of medicines in Mexico is the Comisión Federal para la Protección contra Riesgos Sanitarios. In the past, Mexico lacked any specific regulatory pathway for biosimilars. However, in 2009, the Mexican Congress passed Article 222 into the General Health Law, which defined a biosimilar drug, allowing for comparison with an originator biologic. The Comisión Federal para la Protección contra Riesgos Sanitarios created the Evaluation Subcommittee of Biotechnological Products to assess the scientific information submitted for the process of health registration for innovative biotechnological products, including biosimilars. Although the guidelines are not fully developed as of June 2012, the latest version of the guidelines requires preclinical and clinical studies to demonstrate that the quality, safety, and efficacy of the biosimilar are equivalent to those of the original biologic. It also states that once the biosimilar has demonstrated physicochemical comparability, then the scope of clinical trials required for registration can be reduced depending on the type of biosimilar. Our primary research suggests that phase III comparative trials may not be required for biosimilars and the main factor influencing the decision will be the product type. Extrapolation of indications is unlikely to be permitted in the Mexican market.

      Potential issues

      Although there was no regulatory pathway until recently, biosimilars have been available in Mexico for many years. Because of the increasing number of biosimilars coming into the market, the new biosimilar pathway was designed to increase access to biosimilars while maintaining quality, efficacy, and safety. As the regulatory pathway is still fluid, there are a few potential issues that could affect future regulation and subsequent utilization. Thus far only relatively simple biosimilars have been approved for use in Mexico. As the regulatory pathway will most likely depend on the complexity of the biosimilar, more complex biosimilars may be subject to the same clinical trial requirements as the originator biologic, as described in other biosimilar regulatory guidance [

      Federal Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product – Draft Guidance. Rockville, MD: U.S. Department of Health and Human Services, February 2012.

      ]. In 2011, physicians reported cases of anaphylactic shock and skin rashes when using Kikuzubam, a biosimilar analogue of rituximab [

      Milenio. Medicamento biotecnológico del ISSSTE desata pleito legal. Available from: http://jalisco.milenio.com/cdb/doc/impreso/9043982. [Accessed June 14, 2012].

      ]. In 2012, however, despite the safety issues, the State Employees’ Social Security and Social Services Institute (Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado [ISSSTE]) awarded Probiomed a contract worth 190 million Mexican pesos (€11.5 million at current exchange rates) to provide Kikuzubam to state employees over the branded competition [

      Milenio. Medicamento biotecnológico del ISSSTE desata pleito legal. Available from: http://jalisco.milenio.com/cdb/doc/impreso/9043982. [Accessed June 14, 2012].

      ].

      Future environment

      The Mexican government realizes the potential savings associated with biosimilars and expects them to have large discounts relative to the originator biologics [

      Milenio. Firma Calderón regulación para medicamentos biotecnológicos. Available from: http://www.milenio.com/cdb/doc/noticias2011/a651c69e0f2e1c7955fbbca5a8ff2d9d. [Accessed June 6, 2012].

      ]. The government is actively pursuing cost savings through favoring biosimilars over branded agents for government contracts. In addition, the Mexican government will most likely promote the active substitution of biosimilars over the originator biologic. The Mexican biosimilar market should continue to grow and develop in the foreseeable future.

      Chile

      Current situation

      In Chile, the Instituto de Salud Pública is responsible for the scientific evaluation of pharmaceutical products. Until recently, there was no specific regulatory pathway for biosimilars, and all products were required to provide the full complement of clinical studies to gain registration. In 2011, Chile's Agencia Nacional de Medicamentos released draft guidance for the evaluation of biosimilars in Chile. Chile has referenced the European Medicines Agency and WHO guidelines in developing a regulatory pathway for biosimilars [

      Institio de Salud Publica. Gobierno anuncia mesa de trabajo para regular medicamentos biotecnológicos. Available from: http://www.ispch.cl/noticia/14038/gobierno-anuncia-mesa-de-trabajo-para-regular-medicamentos-biotecnologicos. [Accessed June 7, 2012].

      ]. This future regulatory law will ask manufacturers to provide comparative studies with the reference drug to adequately characterize the product and to demonstrate biosimilarity. According to the Chilean expert in our survey, this will most likely include phase I, II, and III comparative studies and may allow for extrapolation of indications.

      Potential issues

      Chile has local production capacity for biologics. As the current regulatory guidelines for biosimilars are in development, the future regulatory landscape remains open. Chile's eventual biosimilar pathway, however, will most likely follow European Medicines Agency or WHO guidelines. Our findings indicate that there may be standardized guidelines for all biosimilars with specific requirements depending on the complexity of the molecule. Safety issues could also influence the future regulatory environment. Recently, there were well-publicized safety issues with the recombinant insulin Wosulin [

      Cooperativa. Polémica por insulina india tiene origen comercial, según director de Asilfa. Available from: http://www.cooperativa.cl/prontus_nots/site/artic/20060202/pags/20060202190746.html. [Accessed June 8, 2012].

      ]. Although potential safety issues might slow down the progress toward developing biosimilar regulatory guidelines, our primary research indicates that the Chilean government seems determined to press forward with a distinct regulatory pathway for biosimilars.

      Future environment

      There is considerable financial pressure to allow access to biosimilars in Chile. Our research suggests that discounts to branded originators are expected to be approximately 30%. As the majority of biosimilars will be purchased by the government, the opportunity for cost savings is significant. Active substitution of biosimilars for biologics will most likely be a widespread policy to ease financial burden. With the pending regulatory framework, the Chilean biosimilar market is positioned to expand in the coming years.

      Venezuela

      Current situation

      The main control body that regulates pharmaceutical products in Venezuela is the Ministerio del Poder Popular para la Salud. Since 2000, requirements for biological products are formally distinct from those for small molecule products. The National Monitoring Biological Products Division, which is a division of the National Hygiene “Rafael Rangel” Institute, is responsible for the analysis of biological products. Current regulations in Venezuela consider that all biological products are new and there is no distinct regulatory pathway for biosimilars. Consequently, complete studies of quality, safety, and efficacy are required for any biotherapeutic product to receive sanitary registration. According to our primary research, Venezuela may emulate the European Medicines Agency, the WHO, or a regional body such as the Agência Nacional de Vigilância Sanitária in creating biosimilar-specific guidelines. As the situation regarding biosimilar pathway development in Venezuela is still emerging, our primary research indicates that preclinical and phase III studies for biosimilars could require clinical studies that would be similar to those of the innovator biologic. In addition, phase I and II trials will most likely be comparative. The extrapolation of indications will most likely not be allowed for biosimilars in Venezuela.

      Potential issues

      Compared with other Latin American countries in the sample, the Venezuelan government has put minimal emphasis on developing a regulatory framework for biosimilars. There are many potential factors that could provoke the introduction of new regulations for biosimilars in Venezuela. Currently, Venezuela has very limited local production capabilities. The one national manufacturer of biotherapeutic products, Quimbiotec, produces only blood by-products. The majority of biotherapeutic products consumed in Venezuela are imported. At this time, there is a significant deficiency of drugs in Venezuela, mainly because of foreign exchange controls. As a result, it is quite difficult for domestic pharmaceutical companies to exchange Venezuelan currency and procure the materials necessary for pharmaceutical production. According to our research, another problem that local biotherapeutic manufactures face is underdeveloped infrastructure in Venezuela to carry out the full complement of clinical trials required for biotherapeutic products. Our primary research suggested that it may take a biotherapeutics manufacturer doing clinical trials in Venezuela up to 7 or 8 years to register a biosimilar product, whereas an international biotherapeutics producer doing clinical trials in another country could register a biosimilar within 1 to 2 years. Thus, the prospect of future local biosimilar production is unpromising, and biosimilars made abroad are expected to be the only biosimilars available in the Venezuelan market. Venezuela's dependence on the international biosimilars market could possibly hinder uptake as the lack of local data may require additional clinical trials in local populations. Another issue that could affect the future biosimilar regulatory environment in Venezuela is safety. Although no major safety issues with biosimilars have been reported in Venezuela, any future safety issues could shape Venezuela's biosimilar regulatory policy, as has been observed in other Latin American countries.

      Future environment

      While Venezuela is still developing a biosimilar-specific regulatory pathway, the opportunity for biosimilar utilization is high. In Venezuela, the high cost of branded biologics has created financial strain on the national pharmacy budget. Accordingly, the government would welcome any cost-saving measure that could alleviate the economic pressure. Our research indicates that biosimilars are expected to carry a 40% discount to the branded product. With these sizeable discounts, it is anticipated that the government will implement an active substitution policy of biosimilars for the innovator biologics.

      Argentina

      Current situation

      Argentina has embraced the use of biosimilars as they have been on the Argentinean market for over a decade. Argentina is also a major manufacturer of biosimilars in the Latin American region. Two organizations are responsible for the evaluation of biosimilars in Argentina. The Administración Nacional de Medicamentos, Alimentos y Tecnología Médica is the regulatory body responsible for the licensing of biosimilars. The Instituto Nacional de Medicamentos is accountable for technical evaluations of biosimilars. In Argentina, legislation establishes that it is not necessary for biosimilars to undergo the same clinical rigor as an innovative drug. Currently, biosimilars are subject to comparative studies with the reference biologic to demonstrate biosimilarity. These comparative studies include preclinical as well as phase I, II, and III studies. Each potential indication for a biosimilar will require clinical studies, and thus extrapolation of indications is not allowed.

      Potential issues

      Argentina has a well-established regulatory pathway for biosimilars; however, there are still some issues that could affect the future regulatory environment. A potential factor that has not been addressed by current regulation is the evaluation of more complex biosimilars such as mAbs. These more complex molecules have not undergone evaluation under the current biosimilar pathway. Our primary research suggests that because of the complex nature of the manufacturing process and additional immunogenicity concerns, complex biosimilars might need to overcome additional regulatory hurdles to gain approval. Another issue that could alter current and future biosimilar regulatory guidelines is safety concerns with the biosimilar. As no safety issues have been previously cited concerning biosimilars in Argentina, the Argentine government has pressed forward with its strong emphasis on allowing access to biosimilars. If there are safety issues in the future, the regulatory requirements could become more rigorous. Regardless of potential changes to the existing biosimilar regulatory framework, the Argentine government is committed to providing access to biosimilars.

      Future environment

      There is strong financial pressure to allow access to biosimilars in Argentina. The Argentine government will continue encouraging the development of biosimilar drugs. Recently, the Ministry of Science, Technology and Productive Innovation announced a subsidy of 20 million pesos to develop mAbs in hopes of lowering state costs [

      Argentina Investiga. La Universidad desarrollará medicamentos contra el cáncer. Available from: http://argentinainvestiga.edu.ar/english/noticia.php?titulo=the_university_will_develop_medicines_to_treat_cancer&id=1269. [Accessed June 11, 2012].

      ]. In addition, our research suggests that biosimilar discounts to branded originators are expected to be approximately 30%, and Argentina will allow for the substitution of biosimilars for branded biologics. The commercial outlook for the Argentine biosimilar market remains positive as the government has plans to advance biotechnology.

      Discussion

      Latin America is a diverse region with a range of perspectives regarding the most appropriate structure for biosimilar regulation. Underlying these perspectives are a number of political, economic, and historic experiences that contribute to the motivation a country may have to evolve policies for reviewing and approving biosimilar drugs, including the desire to support local production capabilities for biosimilars. These factors, coupled with the interaction of local thought leaders with the international community, contribute to the overall level of Biosimilar Emphasis that exists within each country. As a result of such heightened emphasis, Brazil has led the development and implementation of evolved biosimilar regulation within the region with its 2010 resolution RDC 55/2010 that created new regulatory pathways for new biologic products and similar biologic products. Particularly unique within this legislation were the distinct regulatory pathways created for drugs on the basis of the underlying level of complexity inherent to their reference molecules, and the corresponding level of evidence required to sufficiently convince regulators that they provide comparable safety and efficacy to their reference molecules.
      Of these two pathways, the comparability pathway is fairly conventional in its similarity to the requirements brought forward by the WHO Similar Biotherapeutic Products guidelines. The individual development pathway, however, includes reduced requirements, opening the door to lower complexity biosimilar products. Such a pathway deviates from the vision for biosimilars defined by the WHO and is reflective of a hypothesis that has emerged from this research that a conceptual bias may exist within Brazil regarding the appropriate threshold for regulatory requirements for follow-on biologic products. The example in Mexico of the Comisión Federal para la Protección contra Riesgos Sanitarios’ approval of Probiomed's Kikuzubam, which was subsequently purchased by ISSSTE at a discount to branded Rituxan, supports the hypothesis that a similar bias may apply to other countries within the region.
      Safety problems, such as those resulting from the use of Kikuzubam in Mexico and Wosulin in Chile, highlight the need for distinct pathways to regulate review, approval, and pharmacovigilance processes for biosimilars, and argue for greater transparency of government actions to incentivize the domestic production of biologics. Observed safety issues, however, have apparently not had a major impact on governmental actions to increase access to biosimilars in the region to date.
      The success of the two-pathway system coupled with local manufacturing capabilities in Brazil should encourage the production of biosimilars in multiple therapeutic areas and lead to increased utilization. However, there are many factors that could affect biosimilar regulation, for example, the production of more complex molecules, such as mAbs. There will be a big push in Brazil to manufacturer biosimilar mAbs, because these molecules represent 1% of the total amount of biotherapeutic products distributed yet account for 32% of the total amount spent on biological products by the Brazilian government [
      • Castanheira L.G.
      • Barbano D.B.
      • Rech N.
      Current development in regulation of similar biotherapeutic products in Brazil.
      ]. Thus far, no mAbs have been produced in Brazil, and so it is yet to be seen how the manufacturing and data requirements will be handled for these complex molecules.
      Brazil's leadership in the area of biosimilars has likely set the stage for regulators in other Latin American countries to follow. From our research we learned of the potential for Mexico, another country with a significant level of Biosimilar Emphasis, to waive phase III clinical data requirements in the case of lower complexity biosimilar products. Although the sample size of our primary research interviews was small, suggestions of similar deliberations emerged across the countries we investigated. Such lowered requirements are still evolving, but in the face of the political and economic pressures that exist to increase access to health care, and the innovative example of Brazil, the gradual implementation of reduced requirements for less complex biosimilars in Mexico—and followed later in turn by countries with lower Biosimilar Emphasis—seems likely.
      This study should be viewed as an exploratory effort to understand the rapidly evolving regulatory environment for biosimilars. Our small sample size should be viewed in this context. Future research is required to validate and build on the findings presented here.
      In light of the regulatory advances to date—and continued evolution likely in the future—biosimilars offer a significant opportunity to bring much-needed cost savings to public and private payers across Latin America. Expected discounts to branded therapies range from 10% to more than 30%, with utilization expected to be strongest with public sector payers and cash-paying patients. Assuming that evolving regulatory pathways can succeed in ensuring requisite comparability of the safety and efficacy of molecules of varying degrees of complexity, the discounts afforded to these biosimilar therapies should offer interesting cost-effective alternatives for payers and consumers to consider to address their health care needs.

      Acknowledgments

      We thank Daniele Bruni, Nigel Gregson, and Dr. Robert Nordyke of PriceSpective, an ICON plc company, for their thoughtful input throughout the planning, research, and reporting phases of this project.
      Source of financial support: This project was supported by PriceSpective, an ICON plc Company .

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        Current development in regulation of similar biotherapeutic products in Brazil.
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        • World Health Organization
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      3. Federal Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product – Draft Guidance. Rockville, MD: U.S. Department of Health and Human Services, February 2012.

      4. Milenio. Medicamento biotecnológico del ISSSTE desata pleito legal. Available from: http://jalisco.milenio.com/cdb/doc/impreso/9043982. [Accessed June 14, 2012].

      5. Milenio. Firma Calderón regulación para medicamentos biotecnológicos. Available from: http://www.milenio.com/cdb/doc/noticias2011/a651c69e0f2e1c7955fbbca5a8ff2d9d. [Accessed June 6, 2012].

      6. Institio de Salud Publica. Gobierno anuncia mesa de trabajo para regular medicamentos biotecnológicos. Available from: http://www.ispch.cl/noticia/14038/gobierno-anuncia-mesa-de-trabajo-para-regular-medicamentos-biotecnologicos. [Accessed June 7, 2012].

      7. Cooperativa. Polémica por insulina india tiene origen comercial, según director de Asilfa. Available from: http://www.cooperativa.cl/prontus_nots/site/artic/20060202/pags/20060202190746.html. [Accessed June 8, 2012].

      8. Argentina Investiga. La Universidad desarrollará medicamentos contra el cáncer. Available from: http://argentinainvestiga.edu.ar/english/noticia.php?titulo=the_university_will_develop_medicines_to_treat_cancer&id=1269. [Accessed June 11, 2012].

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        Value in Health Regional IssuesVol. 2Issue 2
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          A journal article is sometimes an unfinished piece, which is finished not after the peer review process [1], but after its original publication and the letters sent to the journal by readers and the wider audience. An example of this is the case of the article by Azevedo et al. [2] published in Volume 1, Issue 2, of Value in Health Regional Issues (VIHRI) (focusing on Latin America). After receiving a Letter to the Editors by Dr. Jose Elias Rizk Aziz regarding this article, the editorial team reviewed the article and sent the letter, as well as other comments, to the authors, who promptly responded with a response Letter to the Editors, as well as with an erratum of the original article.
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      • Response to “Potential Regulatory and Commercial Environment for Biosimilars in Latin America” by Azevedo et al.
        Value in Health Regional IssuesVol. 2Issue 2
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          I refer to the article titled “Potential regulatory and commercial environment for biosimilars in Latin America” written by Azevedo et al., published in Value in Health Regional Issues 1 (2012):228–34, which contains incorrect information about biosimilars’ regulation and market environment in Mexico.
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