Brazil: Pharmacovigilance Risk in Evolving Biosimilar Regulation
November 10, 2017

by Roberto Rodrigues The Brazilian Health Surveillance Agency (ANVISA), created in 1999, is responsible for promoting the protection of public health and monitors the manufacturing and marketing of products subject to food and drug rules. Currently, one of the most significant regulatory challenges facing ANVISA is the regulation of biological and biosimilar1 (follow-on biologics) products. At the approval stage, the agency is dealing with a lack of specific guidelines for conducting immunogenicity and other comparability studies and this directly affects the criteria for the approval of biologics and biosimilars. In addition, pharmacovigilance is a critical issue that will become increasingly relevant over the next years due to the Brazilian government’s program for distribution of drugs to the population. Automatic Substitution of Biological Products in the Unified Health System (SUS) ANVISA’s Rule #55 of 2010 establishes the requirements for the granting of marketing authorization to new biological products and follow-on biologics. The rule provides three ways for obtaining marketing authorization as follows: a) The ‘Full data package pathway’ (Art. 25 of Rule #55/2010) requires the submission of a full dossier to obtain marketing authorization for a new biological product. b)The ‘Comparative pathway’ requires the submission of a comparative dossier containing non-clinical and clinical studies in order to demonstrate comparability between the follow on biological product to be approved and the biologics used as comparator. It also requires the submission of studies with information about development and quality control and a comparability result report (providing a comparison to the comparator biologic).These steps are required in order to obtain marketing authorization for a follow-on biological product using this pathway. c) The ‘Individual development pathway’ requires the submission of studies with information about development, production, quality control, and non-clinical /clinical data showing the quality and safety of the product, in order to obtain marketing authorization for a follow-on biological product. The scope of this latter requirement to submit non-clinical /clinical studies will depend on the amount of data for pharmacological properties, the safety and the efficacy of the originator product2. For all three pathways, ANVISA requires the submission of an immunogenicity study report. In addition, Art. 29 of Rule #55/2010, requires the submission of pharmacovigilance and risk management plans before granting marketing authorization. It is worth noting that Rule #55 of 2010 fails to establish criteria for assessing interchangeability between new biological follow-on products. There is no provision in the Rule or in ANVISA’s guidelines addressing substitution or interchangeability3. The lack of a specific provision or guideline addressing substitution and interchangeability between biological products is becoming a problem in Brazil. It is likely that ANVISA will grant the first marketing authorizations for complex follow-on biologics during 2015. At the same time, the government’s program for public drug distribution through SUS continues to treat biological products as identical to small molecules in its substitution policy. Art. 196 of the Brazilian Constitution, establishes health as "everybody’s right and as a duty owed by the State." In view of this provision, the Brazilian government created the Unified Health System, or SUS, by Law #8,080 of 1990. Articles 6 and 7 of this law establish the Brazilian government’s duties regarding healthcare and this also includes duties owed in relation to pharmaceutical products. The most significant impact of this law is that the government has a legal duty to distribute free drugs to the population through the SUS. Therefore, the government purchases expensive drugs for public distribution. The distribution list, which is constantly updated by the government, includes several biological products4. Physicians working in the public hospitals of the Unified Health System are not free to prescribe a specific drug. All the prescriptions must be written using the Brazilian Common Denomination (DCB), which is similar to the INN5.The distribution system based on the DCB (INN) was developed for small molecules in which the generic drug is interchangeable with the reference product6. This system of automatic substitution for small molecule and generic drugs poses no risk to the patient7. However, the position is different for biological products. Here, the automatic substitution of follow-ons for new biological products is not appropriate as patient safety may be at risk8. Unlike small-molecule drugs, biologics generally exhibit high molecular complexity and micro-heterogeneity9. As the public distribution system for biological products only uses the drug’s INN and does not allow physicians to specify the biological product, prescriptions will lead to dispensation of automatic substitutions for biologics. Furthermore, since adverse reaction reports are not mandatory for health professionals, it is hard for a company holding a marketing authorization (MA) for the new biological product, to manage a pharmacovigilance plan that accurately deals with the automatic substitution by SUS10. Although ANVISA has published internal rules setting out that approved biologics are not interchangeable11, neither the Agency nor the Ministry of Health seem to give any consideration to the problem that the public distribution system is set up to generate automatic substitutions without provision for physician discretion. In the European Union, decisions on automatic substitution of biologics are made by each country individually. France was the first European country to allow substitution between biologic products, although it created some restrictions. To date, no other country in the European Union has explicitly authorized the substitution of biologics from different marketing authorization holders. On the contrary, some European countries have already issued rules banning the practice12. Tech Transfer Partnerships Program for Biologics At the end of 2014, the Brazilian Ministry of Health published guidelines redefining the requirements for establishing Public-Private Productive Development Partnerships (PDPs)13. The PDPs program was created to allow private companies to transfer technology for manufacturing and scale-up of pharmaceutical products to public institutions that supply the SUS. Among the drugs subject to PDPs are complex biological products such as infliximab, adalimumab and rituximab. Despite their complexity, multiple PDPs are being established for these biologic products. It is clear that several manufacturers are signing PDPs with public institutions, which will pose a risk in the near future. When these PDPs start to distribute different biologic products in the SUS program, pharmacovigilance problems will arise regarding the monitoring of the use of different biologics by patients and the possibility of automatic substitution without authorization by the physician. This position presents a risk that is currently being ignored by the Brazilian government. In light of the above, there have been several lawsuits filed by patients seeking a specific biological drug that cite the INN and the name of the reference product. However, the judicial orders directing the government to provide the drugs to the patients only cite the INNs,14 potentially creating another pharmacovigilance issue related to automatic substitution. Conclusion In line with global trends, biologics in Brazil currently represent the highest cost in terms of both private and public purchases. The purchases of medicines by the government grew from USD 1.2 billion in 2003 to approximately USD 6 billion in 2013. While biological products represent only 5% of all drugs distributed by the government, they represent 51% of the budget spent annually on medicines by the Ministry of Health. Complex biological products such as monoclonal antibodies and fusion proteins account for 32% of the total budget of the SUS for distribution of drugs. In 2014 alone, approx. USD 600 million was spent by the government to purchase biologics products such as adalimumab (Humira, Abbvie), infliximab (Remicade, Janssen), trastuzumab (Herceptin, Roche) and etanercept (Enbrel, Wyeth). As ANVISA is likely to continue granting further marketing authorization to follow-on biological products in the near future, the lack of specific provisions addressing substitution and interchangeability between biological products is set to become a growing issue for physicians and patients. It is important to develop systematic training and discussion among physicians concerning specific issues regarding biological products. For instance, a study conducted by Brazilian physician Prof. Valderilio Feijó Azevedo, found that rheumatologists lacked information on the meaning of biosimilars (follow-on biological products) and their difference from generic drugs. The study found that:

Only 70% of the [200] interviewees have answered the question about the definition of the most appropriate concept of a biosimilar. Of those answering that question, 34% chose the item that defined a biosimilar as a biologic that demonstrates bioequivalence with the original biodrug, has all preclinical and clinical trials equal to those already performed with the original biodrug, and that, when approved, already has a well-defined immunogenicity.15

The Brazilian government needs to adapt its public drug distribution program to create a specific framework for distribution of biologic products that will be separate and different from the framework used for small molecules. Health authorities around the globe are discussing inappropriate substitutions that can create safety issues. Limiting this discussion to the scope of changing the INN program through nomenclature alone might not be the best option16. Appropriate prescription systems and the development of guidelines indicating which biological products are considered interchangeable, should also be discussed. Pharmacovigilance has become the responsibility of both the manufacturer of the product and of health authorities (such as ANVISA). Therefore, in order to develop the most beneficial system for the patient, it is necessary for both the manufacturer to develop its pharmacovigilance plan and to operate traceability systems and for the government to develop its policy for public drug distribution. If you have any questions or need additional information, please contact us at prevail@localhost/licks/site.

1 The Brazilian legislation does not use the term “biosimilars.” The new biotherapeutic products are called new biological products and the copies are called biological products: a biological product is a biological drug that is not new or is known, containing molecules with known biological activity, already registered in Brazil, and that has undergone all stages of manufacturing (formulation, bottling, lyophilization, labeling, packaging, storage, quality control and release of the biological product batch for use). (Definition provided by Art. 2, XV of Rule #55/2010). 2 Castanheira L. G.; Barbano D. B.; Rech N. Current development in regulation of similar biotherapeutic products in Brazil. Available at 3 While EMA, FDA and WHO are working on draft guidelines for assessing interchangeability between biologics and biosimilars, ANVISA states in its Q&A forum that there are no such guidelines pending publication. 4 Biological products in the Clinical Protocols and Therapeutic Guidelines of the Ministry of Health and SUS (Ordinance #24 of MCTIE): rituximab (Mabthera, Roche), golimumab (Simponi, Schering-Plough), certolizumab (Cimzia, Astrazeneca), abatacept (Orencia, Bristol-Myers), tocilizumab (Actemra, Roche), infliximab (Remicade, Janssen), adalimumab (Humira, Abbott) and etanercept (Enbrel, Wyeth). 5 Article 3 of Law #9,787 of 1999 requires the DCB name. ANVISA Rule # 64 of 2012 contains the DCBs available for SUS. 6 According to the FDA: “Interchangeability” […] designate[s] the situation where scientific data convincingly demonstrates that two products with very similar molecular compositions or active ingredient(s) can be safely substituted for one another and have the same biologic response and not create adverse health outcomes, e.g., generation of a pathologic immune response. Available at 7 Automatic substitution is defined as the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber. European Commission. Consensus Information Paper 2013. What you need to know about Biosimilar Medicinal Products. 8 9 Niederwieser D, Schmitz S. Biosimilar agents in oncology/haematology: from approval to practice. Eur J Haematol. doi: 10.1111/j.1600-0609.2010.01566.x. 10 If the MA is granted, the safety and efficacy will be monitored and evaluated continuously by the pharmacovigilance system of the company holding the MA and by ANVISA (RDC #4 of 2009 provides pharmacovigilance rules for the holders of a human use MA). 11 SNVS/Anvisa/GFARMACOVIGILÂNCIA #6, July 20, 2007. 12 13 14 #3137-65.2014.4.01.3805 – Federal District Court of Minas Gerais; 390-26.2015.4.01.3800 – Federal District Court of Minas Gerais. 15 Azevedo VF et al. Opinion of some Brazilian rheumatologists about biosimilars. Available at 16

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