Biopharmaceuticals for the Treatment of Multiple Sclerosis in Latin America
The availability of biological drugs used in MS in each country is presented in Table 1. In Argentina and Mexico, there are biosimilar interferons and glatiramer acetate or glatiramoids. Costa Rica, Ecuador, and Peru only present glatiramer acetate and biosimilar drugs, and Bolivia only has a biosimilar drug for interferon beta 1a. Brazil, Chile, Colombia, Panama, Uruguay, and Venezuela do not have biosimilar drugs for MS therapy.
Good Practices in the Report and Use of Biosimilars in Latin America
The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have widely regulated in Europe and the USA, respectively, the registration of biosimilar products, applying shorter and less complex approval procedures than those of the original products. However, both agencies require demonstrations of comparability between products assessed regarding quality, efficacy, and safety. The guidelines of the EMA and the FDA regarding biosimilars adopt a stepwise approach for the development of these drugs, applying a comprehensive physicochemical and biological characterization . Moreover, statistical assessments of quality attributes have gained the attention of both organizations, considering that current statistical approaches have serious weaknesses within a range-based hypothesis of comparison . MS is currently not listed as a therapeutic area with approved biosimilar drugs by the EMA , although glatiramoids are in use.
Regulation to register biosimilar drugs in most Latin American countries has become stronger, frequently based on the regulations of the EMA and FDA. All countries in Latin America have an established and regulated pharmacovigilance program from a local regulatory agency (Table 2). Unfortunately, interchangeability among different products takes place often, as negotiations for better prices continue between the government and pharmaceutical companies. It seems more reasonable to avoid the inclusion of products with unproven efficacy and safety into the reimbursement system than to remove them from it if deemed necessary. Cost–benefit studies are more productive than better prices per vial with uncertain outcomes for the patient.
The report by healthcare professionals of adverse effects associated with the use of these drugs is mandatory. In fact, knowledge on adverse effects of the monoclonal antibodies alemtuzumab and daclizumab for MS treatment was a concern to most neurologists evaluated in a recent survey in Latin America . However, most countries in Latin America have multiple agencies to which adverse effects can be reported, which should be integrated for a better outcome .
Brazil has been considered to have one of the most advanced regulations regarding biosimilars, leading the development of this field in Latin America [4, 6]. Argentina is also advanced in the regulation of biosimilar products and is a major manufacturer in Latin America . Other countries, such as Bolivia, are still in the development phase of draft regulations . The biosimilar markets in countries such as Chile, Mexico, and even Venezuela, where foreign exchange controls pose important challenges for pharmaceuticals, are expected to expand . Should a biosimilar interferon beta or a glatiramoid be approved and used in a particular country, interchangeability among products must be avoided.
Risks in Registration and Use of Biosimilars in Latin America
As a result of the prioritization of economic aspects and matters of access to biological drugs, some Latin American countries have implemented flexible requirements for the registry of biosimilars. This allows a reduction in the quantity, extension, or complexity of comparative clinical and non-clinical trials designed to demonstrate efficacy, safety, and immunogenicity prior to obtaining authorization for commercialization. Occasionally, similar criteria as those applied for the approval of generic drugs are applied. Some Latin American countries have implemented a “third approval pathway,” where a biosimilar may be granted approval based only on information published in the literature regarding reference or innovative medications, a decision which has been considered highly risky to the population’s health . Moreover, most Latin American countries do not require clinical trials prior to the approval of biosimilars; these trials are very resource-consuming but in an ideal situation should be conducted after equivalence studies . Nevertheless, a significant number of biosimilar products are available in the market without approval as such by either the EMA or FDA.
In addition, when defining the regulation for biosimilars, any given country must consider its capability to implement what is agreed upon. In Latin America, a proposed solution to this issue is continuing education programs for the technical teams of regulatory agencies . Other studies have emphasized the importance of educational materials from the EMA and the FDA  and training for healthcare professionals of various fields and levels [5, 8]. Ultimately, the prescribing physicians assume the efficacy and safety risks of drugs they have not been properly informed about. This form of “existence-based medicine” is not good for the patient or the physician in charge.
Critical Considerations Regarding Therapeutic Equivalence
Demonstrations of biosimilarity differ significantly from approvals of generic drugs, in which only equivalence needs to be demonstrated. Determining critical quality attributes is an essential step in evaluating biosimilarity . Thus, the process for a biosimilar drug is likely to be more complex and detailed than that of the reference product. The process requires comparable data that are almost superimposable over the reference through “fingerprinting” to detect differences among highly complex molecules. Therefore, an extensive characterization regarding physiochemistry, biology, and immunogenicity is needed before planning trials for efficacy and safety. Regarding MS, few researchers in Latin America have so far been involved in phase III clinical trials, though this number has increased over the past years .
The requirements concerning the need for clinical trials differ among EMA, FDA, and Latin American regulatory agencies. Clinical trials that are needed to determine effectiveness are not clear, because although “head-to-head” studies meet the criteria for evaluating relative efficacy, they are not always requested as a result of the complexity that is necessary for their design, especially with drugs that have already been approved. On the other hand, agencies agree that equivalence, safety, and efficacy of the novel biosimilar should be equal to or higher than the novel drug. The main outcome is the non-inferiority of the new drug. However, the margin for non-inferiority or equivalence is determined case-by-case, since there are no general criteria for all countries .