The compelling business scenario forecast by the pharmaceutical industry encouraged the entrance into the market competition biosimilar producers, focusing initially on interferon production.
In 2004 a Mexican biopharmaceutical enterprise obtained access to the Mexican health institutional and public markets for the first biosimilar β-interferon-1b for MS, follow-on of the brand innovator licensed since 1993. Despite the attractive premise of providing a less expensive, but equally effective and safe product as the innovator medication, local patients support groups and neurologists raised concerns regarding the replacement of the original medication, considering that many patients, particularly beneficiaries of the Mexican Institute of Social Security, were already been treated with the innovator interferon [7]. This concern was compounded by the absence of data from phase I-III studies not available from the proposed new MS product.
Latin America is one of the regions where the advent of biosimilar drugs for MS have exerted a notable impact, not just in the market share, but as integral part of pharmacological products available in the institutional pharmacy formularies in many of the countries of the area. At present there are nine follow-on β-interferon formulations replacing or competing with the three-interferon innovator products [8]. Thus far, the only other biosimilar product which was temporarily available as an anti-CD20 B-cell inhibitor MAB competing directly with Rituximab, was a Mexican product, which was removed from the market in 2014 due to litigation arguing intellectual property rights and lack of clinical studies [9]. Rituximab, despite studies showing efficacy in RMS [10], has not been approved by the FDA for this indication although it is often prescribed off-label. Rituximab is internationally licensed for treatment of rheumatoid arthritis, non-Hodgkin's lymphoma, chronic lymphocytic leukemia and granulomatosis with polyangiitis.
The advent of biosimilar medications in Latin America has been enabled by the effective marketing and distribution of follow-on interferons for MS by several Mexican and Argentinean and one Uruguayan biopharmaceutical companies. Except for a few instances, the approval process of these products have proceeded for the most part unchallenged by the licensing agencies in the region, regardless of the patent status viability of the brand product.
Typically, since biosimilar interferons do not possess their own clinical studies, the companies applying for medicine registration have utilized the extensive data previously obtained by the innovator through their controlled phase Ill clinical trials. In fact, in most cases, the respective package inserts (regulatory prescribing information) read almost verbatim. In this context, regulatory agencies from Latin American countries have adopted the “third approval pathway” granting approval to biosimilars based on literature references from the innovator. If molecular similarity comparable data is provided supporting the follow-on molecule licensing application, data from their own clinical trials are not required. Only five Latin American countries (Brazil, Chile, Colombia, Panama and Venezuela) have health legalization limiting approval of biosimilars if clinical data are not available. An excellent recent paper (Neurology and Therapy, May 2019) [11] addresses practical issues concerning the approval and use of biosimilar drugs for the treatment of multiple sclerosis in Latin America. The study emphasizes the need for regulation, risk management, and pharmacovigilance of these products on the American continent. Increasing prevalence of MS in the world has stimulated local industries to produce follow-on biosimilar medications theoretically to compete (or replace) the original expensive brands manufactured elsewhere. An example of this effort is reflected in Iran, where the frequencies of disease have increased notoriously in recent years. The most recent epidemiologic study showed a prevalence in the Tehran’s area of 101.39 per 100,000 Inhabitants [12]. A small study comparing head-to-head the efficacy and side effects of a weekly intramuscular Iranian version of β-interferon-1a (CinnoVex®) with the brand molecule, disclosed no differences [13]. The Iranian Food and Drug Organization (FDO) licensed this product. The FDO enforces the national pharmaceutical laws as the health department on charge of licensing medicines, and by utilizing preliminary studies, it has approved another nationally-produced biosimilar 13-interferon-1b [14], which is used thus far in limited and on investigational basis.
While these agents are not widely distributed internationally (Iran is not a member of the World Trade Organization), CinnoVex ® has been available in Russia since 2010 after the “Seven Diseases” (Orphan Diseases) Federal Program provided free medications for MS patients living in Moscow. The public and Russian neurological communities, however, have been wary on a perceived reduced efficacy and side effects experienced with foreign-produced biosimilar interferon medications. A study based on patient-event reporting in a Moscow’s cohort comparing CinnoVex® with another biosimilar interferon-1a (subcutaneous Genfaxon®44 mcg) produced by an Argentinean company, disclosed high frequency treatment withdrawal due to perceived clinical failure and subjective intolerance [15]. The Russian government has encouraged local enterprises (i.e., Biocad) to enter the biosimilar industry scenario. These efforts encompass the production of other therapeutic biologicals including the MAB Rituximab indicated in this case strictly for hematologic malignancies and registered in 2014. The Ministry of Health of the Russian Federation licensed in 2017 the first biosimilar β-interferon-1a, 44 mcg by subcutaneous injection three times a week, produced by Biocad. This is the only MS biosimilar product registered in Russia and worldwide developed in accordance with the EMA guidelines.
Reportedly, no statistically meaningful differences in pharmacokinetics (PK) and pharmacodynamics (PD) In phase I studies were detected, while safety and efficacy equivalence to the reference medicine in phase III trials were found. Phase I and II studies are being conducted for a pegylated form of interferon by Biocad [16].
International licensing agencies, FDA, EMA, Health Canada, the Japanese PMDA (Pharmaceuticals and Medical Devices Agency), the UK Medicines and Healthcare Products Regulatory Agency, and others, have produced strict guidelines for approval of biosimilar medicines (including 13-interferons for MS) requiring rigorous preclinical studies, comparable PK and PD with the reference product, and a randomized, controlled, phase III clinical study. In MS trials the Expanded Disability Status Scale (EDSS), other measurements of neurological performance, and MRI parameters must be included in the trial. In theory, for biosimilar medications efficacy and safety should be demonstrated to be at least comparable, “non-inferior” to the innovator. Thus far, these organizations have not approved biosimilars for MS. These guidelines do not apply to NBCD and copies of laboratory synthesized molecules demonstrating bioequivalence. Clinical trials in these cases are not required.